Compound having anti-hcv activity and process for producing the same

ABSTRACT

The object of the present invention is to provide a compound useful for the prevention and treatment of viral infectious diseases, and particularly liver diseases caused by HCV infection due to its having a high degree of replication inhibitory activity against HCV, its production method, an intermediate compound useful for its production and a pharmaceutical composition containing these compounds, and the present invention relates to a compound represented by the formula (I):  
                 
 
(wherein A represents —(CH 2 ) n —, etc.; B represents —(C═O)—, etc.; D represents —(CH 2 ) m —R′, etc.; E represents a hydrogen atom, etc.; G represents —(CH 2 ) p -J, etc.; bond Q represents a single bond or double bond; and R 1 , R 2  and R 3  may be the same or different and each represent a hydrogen atom, etc.), a prodrug thereof or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

The present invention relates to a compound useful for the preventionand treatment of viral infectious diseases, particularly liver diseasescaused by hepatitis C virus (HCV) infection, due to its having a highdegree of replication inhibitory activity against HCV, its productionmethod, an intermediate compound useful for its production and apharmaceutical composition containing these compounds.

BACKGROUND ART

There are currently 100-200 million persons infected with HCV around theworld, and there are estimated to be more than 2 million infectedpersons in Japan. Approximately 50% of these patients progress tochronic hepatitis, approximately 20% of those patients progress tocirrhosis and liver cancer thirty years or more after infection. Roughly90% of the cases of liver cancer are said to be caused by hepatitis C.In Japan, more than 20,000 patients each year die from liver cancerconcomitant to HCV infection.

HCV was discovered in 1989 as the primary causative virus of non-A,non-B hepatitis following transfusion. HCV is an RNA virus having anenvelope, and its genome is composed of a single-stranded (+) RNA. It isclassified as a hepacivirus belonging to the Flavivirus family.

Since HCV avoids the host's immune mechanism for reasons that are as yetunclear, there are many cases in which a sustained infection resultseven when the virus has infected adults having a developed immunemechanism. It then progresses to chronic hepatitis, cirrhosis and livercancer, and there are known to be a large number of patients in whichliver cancer recurs due to inflammation occurring at non-cancerous siteseven if excised surgically.

Accordingly, there is a desire to establish an effective method oftreatment for hepatitis C, and aside from nosotropic methods whichsuppress inflammation through the use of anti-inflammatory drugs, thereis a particularly strong public desire for the development of a drugthat is capable of reducing or eradicating HCV in the liver of theaffected site.

At present, interferon treatment is the only known treatment method thatis effective in eliminating HCV. However, interferon is effective onlyin about one-third of all patients. The efficacy of interferon againstHCV genotype 1b in particular is extremely low. Thus, it is stronglydesired to develop an anti-HCV drug that can be used in place of or incombination with interferon.

In recent years, although ribavirin(1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxyamide) has been soldcommercially as a therapeutic drug for hepatitis C by concomitant usewith interferon, its efficacy remains low, and new hepatitis Ctherapeutic drugs are sought after. In addition, although attempts havebeen made to eliminate the virus by enhancing patient immunity throughthe use of interferon agonists, interleukin-12 agonists and so forth,none of these have been found to be effective.

Ever since cloning of the HCV gene, although molecular biologicalanalyses have progressed rapidly on the mechanisms and functions ofvirus genes and the functions of various viral proteins, mechanismsinvolving virus replication within host cells, sustained infection,pathogenicity and so forth have yet to be fully elucidated. At present,a reliable testing system for HCV infection using cultured cells has notbeen established. Thus, it has so far been required to use substitutevirus assay methods using other analogous viruses when evaluatinganti-HCV drugs.

In recent years however, it has become possible to observe HCVreplication in vitro using a non-structural domain portion of HCV. As aresult, anti-HCV drugs can now be evaluated easily by the replicon assaymethod (Non-Patent Document 1). The mechanism of HCV RNA replication inthis system is considered to be the same as the replication of theentire length of the HCV RNA genome that has infected hepatocytes. Thus,this system can be said to be an assay system that is based on cellsuseful for identifying compounds that inhibit HCV replication.

The inventors of the present invention found that a series of compounds,which are disclosed in International Patent Laid-Open Publication No. WO98/56755 (Patent Document 1), derived from microorganisms such asAureobasidium genus have a high degree of HCV replication inhibitoryactivity as determined according to the aforementioned replicon assaymethod (Japanese Patent Application No. 2003-34056). These inhibitorshave a high potential for use as therapeutic drugs for HCV. However,since this series of compounds is derived from microorganisms, they havethe disadvantage of being difficult to synthesize or only allowing thesynthesis of limited derivatives from naturally-occurring compounds.

Patent Document 1: International Patent Laid-Open Publication No. WO98/56755 pamphlet

Non-Patent Document 1:

V. Lohmann, et al., ed., Science, 1999, Vol. 285, p. 110-113

DISCLOSURE OF THE INVENTION

As a result of extensive research to resolve the aforementionedproblems, the inventor of the present invention found that compounds ofthe present invention have extremely potent anti-HCV replicon activity,have growth inhibitory effects on HCV, exhibit mild cytotoxicity invitro, and are extremely useful as anti-HCV preventive/therapeuticagents, while also found a production method that enables thesecompounds to be synthesized easily, thereby leading to completion of thepresent invention.

The object of the present invention is to provide a compound useful forthe prevention and treatment of viral infections, and particularly liverdiseases caused by hepatitis C virus (HCV) infection due to its having ahigh degree of replication inhibitory activity against HCV, itsproduction method, an intermediate compound useful for its productionand a pharmaceutical composition containing these compounds.

The present invention relates to a method for producing a compoundrepresented by the formula (I):

(wherein A represents —(CH₂)_(n)—, where n represents an integer of 0 to10;

B represents —CH₂—, —(C═O)—, —CH(OH)—, —CH(NH₂)— or —C(═NOR)—, where Rrepresents a hydrogen atom, a linear or branched alkyl group having 1 to8 carbon atoms (which may be substituted with an amino group that may bemono- or di-substituted with a linear or branched alkyl group having 1to 4 carbon atoms);

D represents —(CH₂)_(m)—R′, where m represents an integer of 0 to 10,and R′ represents a hydrogen atom, a linear or branched alkyl group, alinear or branched alkynyl group, a linear or branched alkenyl group, acycloalkyl group, a cycloalkenyl group, a heterocyclyl group which maybe substituted, an aryl group which may be substituted, a heteroarylgroup which may be substituted, an —OX group (where X represents ahydrogen atom, a linear or branched alkyl group, a linear or branchedalkynyl group, a linear or branched alkenyl group, a cycloalkyl group oran aryl group which may be substituted) or a halogen atom;

E represents a hydrogen atom or a linear or branched alkyl group;

G represents —(CH₂)_(p)-J, where p represents an integer of 0 to 4, andJ represents a hydrogen atom, an OH group, a SH group, a methylthiogroup, a carboxyl group, a carbamoyl group, an amino group, a guanidinogroup, a linear or branched alkyl group, a cycloalkyl group, a linear orbranched alkynyl group, a linear or branched alkenyl group, an arylgroup which may be substituted, a heterocyclyl group which may besubstituted, or a heteroaryl group which may be substituted;

a bond Q represents a single bond or a double bond; and

R₁, R₂ and R₃ may be the same or different, and each represent ahydroxyl group, an amino group (which may be mono- or di-substitutedwith a linear or branched alkyl group having 1 to 4 carbon atoms), —OL,a linear or branched alkyl group, a linear or branched alkenyl group ora linear or branched alkynyl group, where L represents a linear orbranched alkyl group, a linear or branched alkenyl group or a linear orbranched alkynyl group), a prodrug thereof or a pharmaceuticallyacceptable salt thereof;

comprising reacting a compound as the starting compound represented bythe following formula:

(wherein A, D and bond Q have the same meanings as defined above, and Xand Y may be the same or different and each represent a linear orbranched alkyl group or a protecting group of a carboxyl group) with anα-amino acid ester represented by the following formula:

(wherein E and G have the same meanings as defined above, and Zrepresents a linear or branched alkyl group or a protecting group of acarboxyl group) in the presence of a base and a coupling agent, to yielda compound represented by the following formula:

(wherein A, D, E, G, bond Q, X, Y and Z have the same meanings asdefined above), and then subjecting this compound to hydrolysis,reduction, amination or amidation, hydroxyimination and/or esterconversion, if desired, to obtain the desired compound of the formula(I).

Moreover, the present invention relates to a method for producing acompound represented by the following formula:

(wherein D and n have the same meanings as defined for the above formula(I), M₁ and M₂ may be the same or different and each represent an oxygenatom or a sulfur atom, and P and P′ may be the same or different andeach represent a hydroxyl protecting group), comprising reacting acompound represented by the following formula:

(wherein P and P′ have the same meanings as defined above) with acompound represented by the following formula:

(wherein D, n, M₁ and M₂ have the same meanings as defined above).

Moreover, the present invention relates to a compound represented byformula (I):

(wherein A, B, D, E, G, bond Q, R₁, R₂ and R₃ have the same meanings asdefined for the above formula (I)), a prodrug thereof or apharmaceutically acceptable salt thereof.

Moreover, the present invention relates to a compound of theaforementioned formula (I), its prodrug or pharmaceutically acceptablesalt thereof, wherein in the case n represents 6, D represents an-heptyl group and p represents 1, then J represents a group which isneither a phenyl group (the phenyl group is substituted with an —OWgroup at the p-position where W represents a hydrogen atom, a linear orbranched alkyl group, or a linear or branched alkenyl group) nor a3-indolyl group.

Moreover, the present invention relates to a compound of theaforementioned formula (I), its prodrug or pharmaceutically acceptablesalt thereof, wherein in the case n represents 6, D represents an-heptyl group and p represents 1, then J represents a group which isneither a phenyl group (the phenyl group is substituted with an —OWgroup at the p-position where W represents a hydrogen atom, a linear orbranched alkyl group, a linear or branched alkenyl group or a linear orbranched alkynyl group) nor a 3-indolyl group.

Moreover, the present invention relates to a compound represented by thefollowing formula:

(wherein P and P′ may be the same or different and each represent ahydroxyl protecting group).

Moreover, the present invention relates to a compound represented by thefollowing formula:

(wherein A, D, X and Y have the same meanings as previously definedabove).

Moreover, the present invention relates to a pharmaceutical compositioncontaining a compound of the aforementioned formula (I), a prodrugthereof or a pharmaceutically acceptable salt thereof.

Moreover, the present invention relates to the aforementionedpharmaceutical composition for preventing or treating a viral infectiousdisease.

Moreover, the present invention relates to the aforementionedpharmaceutical composition wherein the viral infectious disease is aninfectious disease by HCV.

Moreover, the present invention relates to the aforementionedpharmaceutical composition wherein the infectious disease by HCV ishepatitis C, cirrhosis, liver fibrosis or liver cancer.

Since the compounds of the present invention have extremely potentanti-HCV activity and HCV growth inhibitory effects, and exhibit mildcytotoxicity in vitro, a pharmaceutical composition containing acompound of the present invention is extremely useful as an anti-HCVpreventive/therapeutic agent.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present description, linear or branched alkyl groups refer tolinear or branched hydrocarbon groups having 1 to 12 carbon atoms, andpreferably linear or branched hydrocarbon groups having 1 to 7 carbonatoms, unless defined otherwise in the present description. Examples oflinear or branched alkyl groups include a methyl group, an ethyl group,a propyl group, an isopropyl group, a n-butyl group, an isobutyl group,a t-butyl group, a pentyl group and a heptyl group. In addition,cycloalkyl groups refer to cyclic hydrocarbon groups having 3 to 8carbon atoms, examples of which include a cyclopentyl group, acyclohexyl group, and a cycloheptyl group. Cycloalkenyl groups refer tocyclic hydrocarbon groups having 3 to 8 carbon atoms and containing atleast one double bond, examples of which include a cyclohexenyl group.In addition, linear or branched alkenyl groups refer to linear orbranched hydrocarbon groups having 2 to 8 carbon atoms and containing atleast one double bond, examples of which include a vinyl group, a1-propenyl group, an allyl group, a 2-butenyl group, and a2-ethenyl-2-butenyl group. The linear or branched alkynyl groups referto linear or branched hydrocarbon groups having 2 to 8 carbon atoms andcontaining at least one triple bond, examples of which include anethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynylgroup, a 3-butynyl group, a 2-pentynyl group, a 3-pentynyl group, a4-pentynyl group, a 2-hexynyl group, a 4-hexynyl group, a 2-decynylgroup, a 6,6-dimethyl-hepta-2,4-diyn-1-yl group.

In addition, the heterocyclyl groups described in the presentdescription refer to a 4 to 6 membered mono-cyclic or 7 to 10 membereddi-cyclic group (preferably a monocyclic group) containing as ringmembers 1 to 4 (and preferably 1 or 2) heteroatoms independentlyselected from a nitrogen atom, a sulfur atom and an oxygen atom andwhich may have at least one double bond, specific examples of whichinclude groups derived from pyran, morpholine, tetrahydrofuran,dihydrofuran, tetrahydropyran, dihydropyran, 1,3-dioxane, piperazine,piperidine and thiomorpholine.

The aryl groups described in the present description refer to anaromatic monocyclic or polycyclic hydrocarbon group, specific examplesof which include groups derived from benzene, naphthalene, anthraceneand fluorene.

The heteroaryl groups described in the present description refer to a 4to 6 membered mono-cyclic or 7 to 10 membered di-cyclic aromatic group(preferably a monocyclic group) containing as ring members 1 to 4 (andpreferably 1 or 2) heteroatoms independently selected from a nitrogenatom, a sulfur atom and an oxygen atom, specific examples of whichinclude groups derived from furan, thiophene, pyrrole, pyrazole,pyridine, thiazole, imidazole, pyrimidine, indole, quinoline, oxazole,isoxazole, pyrazine, triazole, thiadiazole, tetrazole and pyrazole.

The aralkyl groups described in the present description refer to theaforementioned linear or branched alkyl groups substituted with theaforementioned aryl groups, specific examples of which include a benzylgroup and a phenethyl group.

The heteroarylalkyl group described in the present description refer tothe aforementioned linear or branched alkyl groups substituted with theaforementioned heteroaryl groups.

The acyl group described in the present description refer to theaforementioned linear or branched alkyl, aryl, heteroaryl orheterocyclyl groups which are bonding via a carbonyl group.

The term “may be substituted” described in the present descriptionrefers to the group described in this manner being substituted with agroup such as a linear or branched alkyl group, a linear or branchedalkoxy group, a linear or branched alkenyl group, a linear or brancedalkenyloxy group, a linear or branched alkynyl group, a linear orbranched alkynyloxy group, a cycloalkyl group, a cycloalkyloxy group, acyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxygroup, a halogen atom, an aryl group, an aryloxy group, a heteroarylgroup, a heteroaryloxy group, an aralkyl group, an aralkyloxy group, anamino group (which may be mono- or di-substituted with a linear orbranched alkyl group), an acyl group, a linear or branched alkylsulfonylgroup, a carbamoyl group, a linear or branched alkylthio group, acarboxyl group, a linear or branched alkylcarbonyl group, a formyl groupor an aminosulfonyl group, unless specifically defined otherwise in thepresent description. The aryl and heteroaryl moieties in thesesubstituent groups may further be mono-, di- or tri-substituted with ahalogen atom, a linear or branched alkyl group, a linear or branchedalkoxy group, a linear or branched alkenyl group, a linear or branchedalkenyloxy group, a linear or branched alkynyl group, a linear orbranched alkynyloxy group, a cycloalkyl group, a cycloalkyloxy group, acyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxygroup, an aryl group, an aryloxy group, a heteroaryl group, an aralkylgroup, an aralkyloxy group, an amino group which may be mono- ordi-substituted with a linear or branched alkyl group; an acyl group, alinear or branched alkylsulfonyl group, a linear or branched alkoxygroup, a carbamoyl group, a linear or branched alkylthio group, acarboxyl group, a linear or branched alkylcarbonyl group, a formyl groupor an aminosulfonyl group.

The protecting group described in the present description refers to agroup for protecting a reactive functional group from an undesiredchemical reaction that can be easily removed following completion of thereaction. The protecting group differs according to the type offunctional group to be protected, and in the case of protecting ahydroxyl group, for example, groups such as a t-butyldiphenylsilylgroup, a tetrahydropyranyl group, a methoxymethyl group, a benzyl group,a trimethylsilyl group, a p-methoxybenzyl group or at-butyldimethylsilyl group can be used preferably. In the case ofprotecting a carboxyl group, various protecting groups, for example, asdescribed in “Protective Groups in Organic Synthesis”, the 3rd edition(John Wiley & Sons, Inc., 1999) or “Organic Synthesis ExperimentalMethod Handbook” (Maruzen, 1990) can be used. As a protecting group of acarboxyl group, for example, a methyl group, an ethyl group, a t-butylgroup, an allyl group, a phenyl group, a benzyl group, and varioussubstituted silyl groups (such as trimethylsilyl and triethylsilyl) canbe used.

The prodrug described in the present description refers to a derivativeof the compound of formula (I) that has been chemically modified so asto be able to be converted to a compound of formula (I) or apharmaceutically acceptable salt thereof either under physiologicalconditions or by solvolysis following administration as apharmaceutical. Although the prodrug may be inert when administered to apatient, it is present in the body after being converted to the activecompound of formula (I). Examples of prodrugs include compounds thathave undergone C₁₋₆ alkylesterification, C₁₋₆ alkenylesterification,C₆₋₁₀ arylesterification, C₁₋₆ alkyloxy C₁₋₆ alkylesterification(formula given below) or C₁₋₆ alkoxyesterification (formula given below)of the carboxylic acid portion of this compound.

Furthermore, the term “treatment” described in the present descriptionincludes the elimination or alleviation of HCV, inhibition of thefurther spread of HCV, and alleviation of symptoms caused by HCVinfection by administering the pharmaceutical composition of the presentinvention to a subject. Examples of symptoms caused by HCV infectioninclude hepatitis C, cirrhosis, liver fibrosis and liver cancer.

The following provides a detailed description of compounds of thepresent invention.

Although the compound of the present invention is a compound representedby the aforementioned formula (I), a prodrug thereof or apharmaceutically acceptable salt thereof, it is preferably a compoundrepresented by the aforementioned formula (I) wherein, in the case n is6, D represents a n-heptyl group, and p is 1, then J represents a groupwhich is neither a phenyl group (the phenyl group is substituted with an—OW group at the p-position where W represents a hydrogen atom, a linearor branched alkyl group, a linear or branched alkenyl group or a linearor branched alkynyl group) nor a 3-indolyl group.

In the compound represented by formula (I) of the present invention, Arepresents —(CH₂)_(n)— wherein n is an integer of 0 to 10, preferably aninteger of 2 to 8 and more preferably an integer of 4 to 8.

In addition, in the compound represented by formula (I), although Brepresents —(C═O)—, —CH(OH)—, —CH(NH₂)— or —C(═NOR)—, it preferablyrepresents —(C═O)— or —CH(OH)—.

In addition, in the compound represented by formula (I), D represents—(CH₂)_(m)—R′ where m represents an integer of 0 to 10 and preferably aninteger of 3 to 8. In addition, although R′ represents a hydrogen atom,a linear or branched alkyl group, a cycloalkyl group, a cycloalkenylgroup, a linear or branched alkynyl group, a linear or branched alkenylgroup, a heterocyclyl group which may be substituted, an aryl groupwhich may be substituted, a heteroaryl group which may be substituted,an —OX group (where X represents a hydrogen atom, a linear or branchedalkyl group, or a protecting group of a carboxyl group) or a halogenatom, R′ preferably represents a hydrogen atom, a linear or branchedalkyl group, a linear or branched alkenyl group, a cycloalkyl group or.an aryl group which may be substituted (and particularly preferably aphenyl group).

D particularly preferably represents a n-pentyl group, a n-hexyl group,a n-heptyl group, a n-octyl group, a n-pentenyl group or a 2-methylhexylgroup.

In addition, in the compound of formula (I), although E represents ahydrogen atom or a linear or branched alkyl group, it preferablyrepresents a.hydrogen atom.

In addition, in the compound of formula (I), although G represents—(CH₂)_(p)-J, where p represents an integer of 0 to 4, preferably aninteger of 0 to 2 and particularly preferably 1. In addition, Jrepresents a hydrogen atom, an OH group, an SH group, a methylthiogroup, a carboxyl group, a carbamoyl group, an amino group, a guanidinogroup, a linear or branched alkyl group, a cycloalkyl group, a linear orbranched alkynyl group, a linear or branched alkenyl group, an arylgroup which may be substituted, a heterocyclyl group which may besubstituted, or a heteroaryl group which may be substituted, itpreferably represents an aryl group which may be substituted, and morepreferably a phenyl group (and particularly preferably a phenyl groupthat is substituted at the position p). In addition, the aryl groupwhich may be substituted may be mono-, di- or tri-substituted with agroup selected from an aryl group, an aryloxy group, an arylthio group,an arylamino group, an aralkyloxy group, a heteroaryl group, an aralkylgroup, a heterocyclyl group, a heterocyclyloxy group (the aryl,heteroaryl or heterocyclyl moieties of these aryl, aryloxy, arylthio,arylamino, aralkyloxy, heteroaryl, aralkyl, heterocyclyl, andheterocyclyloxy groups may be additionally mono-, di- or tri-substitutedwith a group selected from a linear or branched alkyl group, a linear orbranched alkenyl group, a linear or branched alkynyl group, a linear orbranched alkoxy group, a linear or branched alkynyloxy group, a linearor branched alkyloxycarbonyl group, a cycloalkyloxy group, atrifluoromethyl group, a cyano group, a halogen atom, a nitro group, anamino group which may be mono- or di-substituted with a linear orbranched alkyl group, an acyl group, a linear or branched alkylsulfonylgroup, a carbamoyl group, a linear or branched alkylthio group, acarboxyl group, a linear or branched alkylcarbonyl group, a formylgroup, an aminosulfonyl group which may be mono- or di-substituted witha linear or branched alkyl group, etc.), a linear or branched alkylgroup, a linear or branched alkenyl group, a linear or branched alkynylgroup, a linear or branched alkoxy group (which may be substituted withan amino group which may be mono- or di-substituted with a linear orbranched alkyl group; a heteroaralkylamino group, or a heterocyclylgroup), a linear or branched alkenyloxy group, a linear or branchedalkynyloxy group (which may be substituted with a dialkylamino group), acycloalkyloxy group, a trifluoromethyl group, a trifluoromethoxy group,a cyano group, a halogen atom, a nitro group, an amino group which maybe mono- or di-substituted with a linear or branched alkyl group, anaminoalkyl group (which may be substituted with an aralkyloxycarbonylgroup), a guanidino group, an arylamino group, an azido group, an acylgroup, a linear or branched alkylsulfonyl group, a linear or branchedalkylsulfonylamino group, a carbamoyl group, a linear or branchedalkylthio group, a carboxyl group, a linear or branchedalkylcarbonylamino group, a linear or branched alkylcarbonyl group, aformyl group, etc.

Preferable examples of G include an aralkyl group which may besubstituted, and particularly a benzyl group which may be substituted,and a particularly preferable example is a benzyl group that issubstituted at the p position.

In addition, in the compound represented by the formula (I), R₁, R₂ andR₃ may be the same or different, and each represent a hydroxyl group, anamino group (which may be mono- or di-substituted with a linear orbranched alkyl group having 1 to 4 carbon atoms), —OL, a linear orbranched alkyl group, a linear or branched alkenyl group or a linear orbranched alkynyl group.

The particularly preferable example of R₁, R₂ and R₃ is a hydroxylgroup.

The following lists preferable examples of the compound represented bythe formula (I) of the present invention.

Of the compound represented by the formula (I) particularly preferableare compounds (15), (16), (17), (18), (19), (20), (21), (22), (23),(24), (25), (26), (27), (28), (29), (30), (31), (33), (38), (39), (40),(41), (42), (43), (44), (45), (48), (49), (50), (51), (52), and (62).

In addition, the present invention relates to a method for producing acompound represented by the formula (I):

(wherein, A, B, D, E, G, R₁, R₂ and R₃ have the same meanings as definedabove), a-prodrug thereof or a pharmaceutically acceptable salt thereof;

comprising reacting as the starting compound a compound represented bythe formula:

(wherein A and D have the same meanings as defined above, and X and Ymay be the same or different and each represent a linear or branchedalkyl group) with an α-amino acid ester represented by the formula:

(wherein E and G have the same meanings as defined above, and Zrepresents a linear or branched alkyl group or a protecting group of acarboxyl group) in the presence of a base and a coupling agent to yielda compound represented by the formula:

(wherein A, D, E, G, X, Y and Z have the same meanings as definedabove), and then subjecting this compound to hydrolysis, reduction,amination or amidation, hydroxyimination and/or ester conversion, ifdesired to obtain the desired compound of the formula (I).

The following provides an explanation of an example of a method forsynthesizing a compound represented by the formula (I) of the presentinvention using the following reaction scheme.

General Production Method 1

In the aforementioned formulas, each of the symbols has the samemeanings as defined in the aforementioned formula (I), and P, P′ and P″each represent a hydroxyl protecting group. The starting compound in theform of Compound 1 can be synthesized in accordance with a methoddescribed in the literature (J. Org. Chem. 1989, 45, 5522, B.E. Marron,et al).

Step 1-1

After reacting Compound 1 with a reducing agent such asbis(2-methoxyethoxy)aluminum sodium hydride or aluminum lithium hydridein a solvent such as various ethers such as diethyl ether,tetrahydrofuran or dioxane, or benzene, toluene or cyclohexane or mixedsolvent thereof at room temperature or while cooling and preferablybelow ice temperature, Compound 2 can be obtained by treating withiodine while cooling and preferably at a temperature of −78° C.

Step 1-2

Compound 2 is then reacted with dihydropyran in a solvent such asdiethyl ether, toluene, cyclohexane, methylene chloride, chloroform,1,2-dichloroethane or ethyl acetate or mixed solvent thereof and in thepresence of a catalytic amount of acid such as pyridiniumpara-toluenesulfonate, toluenesulfonic acid, methanesulfonic acid,acetic acid, trifluoroacetic acid, or dilute hydrochloric acid either atroom temperature or while cooling and preferably below ice temperatureto obtain Compound 3.

Step 1-3

Compound 3 is reacted with a strong base such as tert-butyl lithium,n-butyl lithium or sec-butyl lithium in a solvent such as various etherssuch as diethyl ether, tetrahydrofuran or dioxane, or benzene, tolueneor cyclohexane or a mixed solvent thereof at room temperature or whilecooling, and preferably at a temperature of −78° C, followed by theaddition of formaldehyde and allowing to react while cooling andpreferably below ice temperature to obtain Compound 4.

Step 1-4

Compound 4 is reacted with tert-butyl diphenyl chlorosilane in a solventsuch as N,N-dimethylformamide, tetrahydrofuran, methylene chloride orchloroform or a mixed solvent thereof and in the presence of a base suchas imidazole, trimethylamine or pyridine either at room temperature orwhile cooling and preferably below ice temperature to obtain Compound 5.

Step 1-5

Compound 5 is reacted in various alcohol solvents such as ethanol,methanol or propanol and in the presence of a catalytic amount of acidsuch as pyridinium para-toluenesulfonate, toluenesulfonic acid,methanesulfonic acid, acetic acid, trifluoroacetic acid or dilutehydrochloric acid at room temperature or while heating and preferablywhile reflux heating to obtain Compound 6.

Step 1-6

Compound 6 is reacted with a peroxide such as tert-butyl hydroperoxideor cumene hydroperoxide in a solvent such as methylene chloride orchloroform or a mixed solvent thereof and in the presence of a Lewisacid such as titanium tetraisopropoxide or titanium tetrabutyloxide andL-(+)-diethyl tartrate, L-(+)-dipropyl tartrate, D-(−)-diethyl tartrateor D-(−)-dipropyl tartrate at room temperature or while cooling andpreferably while cooling to obtain Compound 7.

Step 1-7

After hydrometallation (such as hydrozilconation or hydroboration) ofthe triple bond of the compound represented by the formula:

having a desired chain A (—(CH₂)_(n)—) and group D that was synthesizedin General Production Method 2 to be described later, a vinyl metalderivative obtained by transmetallation (by using, for example,Grignard's reagent and dialkyl zinc) is reacted with Compound 7 in asolvent such as various ethers such as diethyl ether, tetrahydrofuran ordioxane, or benzene, toluene or cyclohexane or mixed solvent thereof atroom temperature or while cooling and preferably at a temperature of−78° C. to obtain Compound 8.

Step 1-8

Compound 8 is reacted with 2,2-dimethoxypropane or acetone and so forthin a solvent such as diethyl ether, toluene, hexane, methylene chloride,chloroform or 1,2-dichloroethane or a mixed solvent thereof and in thepresence of a catalytic amount of acid such as pyridiniumpara-toluenesulfonate, toluenesulfonic acid, methanesulfonic acid,acetic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid atroom temperature or while cooling and preferably at room temperature toobtain Compound 9.

Step 1-9

Compound 9 is reacted in a solvent such as diethyl ether,tetrahydrofuran, hexane, methylene chloride or chloroform or a mixturethereof and in the presence of tetrabutylammonium fluoride, hydrofluoricacid, acetic acid or dilute hydrochloric acid and so forth at roomtemperature or while cooling to obtain Compound 10.

Step 1-10

Compound 10 is subjected to an oxidation reaction using manganeseperoxide, nitric acid or Jones oxidation and so forth to obtain thecorresponding dicarboxylic acid. Alternatively, Compound 10 is subjectedto an oxidation reaction using potassium permanganate, Swern'soxidation, Collins oxidation or TEMPO oxidation and so forth to obtainthe corresponding dialdehyde. Preferably, after allowing Compound 10 toreact in a solvent such as methylene chloride or chloroform and in thepresence of oxazyl chloride and dimethyl sulfoxide while cooling andpreferably at −78° C., it is treated with a base such as triethylamineto obtain a dialdehyde. The resulting product can then be converted to adicarboxylic acid by an oxidizing agent such as potassium permanganate,sodium chlorite or chromic acid. Preferably, dicarboxylic acid isobtained by reacting with an aqueous solution of sodium chlorite andsodium dihydrogenphosphate in 2-methyl-2-propanol and 2-methyl-2-buteneat room temperature or while cooling and preferably while cooling. Theresulting product is then reacted in N,N-dimethylformamide di-tert-butylacetal or with tert-butyl 2,2,2-trichloroacetoimidate in a solvent suchas N,N-dimethylformamide, diethyl ether, tetrahydrofuran, hexane,methylene chloride or chloroform, a mixed solvent thereof or in theabsence of solvent at room temperature or while heating to obtainCompound 11.

Step 1-11

Compound 11 is allowed to react in a solvent such as tetrahydrofuran ordioxane or mixed solvent thereof and in the presence of water and anacid such as pyridinium para-toluenesulfonate, methanesulfonic acid oracetic acid at room temperature or while cooling and preferably at roomtemperature to obtain Compound 12.

Step 1-12

Compound 12 can be converted to the corresponding dicarboxylic acid byan oxidation reaction using manganese peroxide, nitric acid or Jonesoxidation and so forth. Preferably, Compound 12 is reacted with Jonesreagent in acetone at room temperature or while cooling and preferablywhile cooling to obtain Compound 13.

Step 1-13

A coupling reagent such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, water-soluble carbodiimide hydrochloride (WSC-HCl)or 1-hydroxybenzotriazole (HOBt) is allowed to act on Compound 13 andα-amino acid tert-butyl ester hydrochloride in a solvent such asN,N-dimethylformamide, tetrahydrofuran, diethyl ether, methylenechloride or chloroform or mixed solvent thereof and in the presence of abase such as N,N-diisopropylethylamine, triethylamine, pyridine or4-N,N-dimethylaminopyridine at room temperature or while cooling andpreferably at room temperature to obtain Compound 14-A, which is onemode of a compound of formula (I).

Step 1-14

Compound 14-A is allowed to react in a solvent such as ethyl ether,tetrahydrofuran, dioxane, hexane, methylene chloride, chloroform, ethylacetate or water or mixed solvent thereof and in the presence or absenceof anisole and in the presence of an acid such as methanesulfonic acid,acetic acid, trifluoroacetic acid or dilute hydrochloric acid at roomtemperature or while cooling and preferably at room temperature toobtain Compound 14-B, which is one mode of a compound of the formula(I).

In order to obtain compounds of the formula (I) of the present inventionother than Compound 14-A and Compound 14-B as above, by using Compound14-A or Compound 14-B as the starting material and subjectinghydrolysis, reduction, amination or amidation, hydroxyimination and/orester conversion if desired, the desired compound of the formula (I) canbe obtained. In addition, a compound of the formula (I) in which bond Qis a single bond can be obtained by hydrogenating Compound 14-A orCompound 14-B in a solvent such as methanol, ethanol, ethyl acetate ortetrahydrofuran and in the presence of a catalyst such as palladiumcarbon, palladium hydroxide, Raney nickel or platinum oxide at roomtemperature or under heating conditions.

The present invention also relates to a method for producing a compoundrepresented by the formula:

(wherein D and n have the same meanings as defined above, M₁ and M₂ maybe the same or different and each represent an oxygen atom or sulfuratom, and P and P′ may be the same or different and each represent ahydroxyl protecting group), which is a useful intermediate compound forsynthesizing a compound of the formula (I), comprising reacting acompound represented by the formula:

(wherein P and P′ have the same meanings as defined above) with acompound represented by the formula:

(wherein D, n, M₁ and M₂ have the same meanings as defined above). Thismethod is the method of step 1-7 in the aforementioned GeneralProduction Method 1.

The following provides an explanation of a method for producing acompound:

that is one of the intermediate compounds for synthesizing theaforementioned compound of the formula (I), using the following reactionscheme.

General Production Method 2

Step 2-1

A coupling reagent such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, water-soluble carbodiimide hydrochloride (WSC-HCl)or 1-hydroxybenzotriazole (HOBt) is allowed to act on Compound a havinga terminal triple bond and a desired chain A (—CH₂)_(n)—) andN,O-dimethylhydroxylamine hydrochloride in a solvent such as diethylether, tetrahydrofuran, dioxane, hexane, methylene chloride, chloroformor ethyl acetate or a mixed solvent thereof and in the presence of abase such as N,N-diisopropylethylamine, triethylamine, pyridine or4-N,N-dimethylaminopyridine at room temperature to obtain Compound b.

Step 2-2

Compound b obtained in the aforementioned step is allowed to react withGrignard's reagent or alkyl lithium In the above formula, P′″ representsa protecting group of a carboxyl group; P″″ represents a protectinggroup of an amino group; and M represents a linear or branched alkylgroup, a linear or branched alkynyl group, a linear or branched alkenylgroup or a cycloalkyl group.

Step 3-1

Compound BB can be obtained by protecting Compound AA with a protectinggroup of the amino group such as acetyl, trifluoroacetyl,t-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethylcarbonyl. Thereaction conditions at this time are appropriately selected depending onthe kind of the protecting group P″″.

Step 3-2

Compound CC can be obtained by reacting Compound BB with M substitutedby a halogen or a leaving group such as methanesulfonate ester andtoluenesulfonate ester at room temperature or under heating, preferablyat room temperature in the presence of a base such as potassiumcarbonate, sodium hydroxide and sodium hydride in a solvent such asdiethyl ether, toluene, cyclohexane, acetone, dimethylformamide,dioxane, ethyl acetate and dimethyl sulfoxide or a mixture solventthereof. Alternately, Compound CC can be obtained by reacting CompoundBB with M substituted by a hydroxyl group under the Mitsunobu's reactionconditions.

Step 3-3

Compound DD can be obtained by deprotecting the protecting group P″″ ofthe amino group of Compound CC. The reaction conditions at this time areappropriately selected depending on the kind of the protecting groupP″″.

General Production Method-4

reagent having a desired group D in a solvent such as diethyl ether,tetrahydrofuran, dioxane or hexane or a mixed solvent thereof at roomtemperature or while cooling and preferably while cooling to obtainCompound c into which the group D has been introduced.

Step 2-3

Compound c obtained in the aforementioned step and ethylene glycol areallowed to react while azeotropic removal of the water that forms whileheating in a solvent such as benzene, toluene or 1,2-dichloroethane andin the presence of an acid such as pyridinium para-toluenesulfonate,para-toluenesulfonic acid, methanesulfonic acid or acetic acid to obtainCompound d.

Compound d obtained here can be used in Step 1-7 of General ProductionMethod 1 that shows a production process of the aforementioned Compound(I). Be noted that, a compound equivalent to Compound d in which M₁and/or M₂ are sulfur atoms can be obtained by a method known to a personwith ordinary skill in the art.

The compound which is a starting compound for synthesizing the compoundsof the above formula (I) and is represented by the formula:

may be synthesized by a method known to a skilled person or by one ofthe reaction schemes of General Production Method-3 to -5 below.

General Production Method-3

In the above formula, P′″ represents a protecting group of a carboxylgroup; P″″ represents a protecting group of an amino group; T representsa leaving group such as sulfonate ester; and U represents an aryl whichmay be substituted or a heteroaryl group which may be substituted.

Step 4-1

Compound EE can be obtained by reacting Compound BB with methanesulfonicacid chloride, toluenesulfonic acid chloride or trifluoromethanesulfonicacid anhydride at room temperature or under cooling, preferably undercooling in the presence of a base such as N,N-diisopropylethylamine,triethylamine, pyridine and 4-N,N-dimethylaminopyridine in a solventsuch as diethyl ether, toluene, cyclohexane, acetone, dimethylformamide,dioxane, ethyl acetate and dimethyl sulfoxide or a solvent mixturethereof.

Step 4-2

Compound FF can be obtained by reacting Compound EE with an aryl- orheteroarylboronic acid derivative or an aryl- or heteroarylboronic acidester derivative at room temperature or under heating, preferably underheating in the presence of a palladium catalyst such as palladiumdiacetate and tetrakistriphenylphosphine palladium in a solvent such asdiethyl ether, toluene, benzene, dimethylformamide, dioxane, ethylacetate, acetonitrile and water or a solvent mixture thereof.

Step 4-3

Compound GG can be obtained by deprotecting the protecting group P″″ ofthe amino group of Compound FF. The reaction conditions at this time areappropriately selected depending on the kinds of the protecting groupP′″.

General Production Method-5

In the above formula, P′″ represents a protecting group of a carboxylgroup; P″″ represents a protecting group of an amino group; and Urepresents an aryl which may be substituted or a heteroaryl group whichmay be substituted.

Step 5-1

Compound HH can be obtained by reacting Compound BB with an aryl- orheteroarylboronic acid derivative, an aryl or heteroarylboronic acidester derivative or a halogenated aryl or halogenated heteroarylderivative at room temperature or under heating, preferably underheating in the presence of a base such as sodium hydride and potassiumcarbonate or a base such as N,N-diisopropylethylamine, triethylamine,pyridine and 4-N,N-dimethylaminopyridine and a catalyst such as copper(II) diacetate and copper (I) iodide in a solvent such as diethyl ether,toluene, cyclohexane, acetone, dimethylformamide, dioxane, methylenechloride, chloroform and dimethyl sulfoxide or a solvent mixturethereof.

Step 5-2

Compound II can be obtained by deprotecting the protecting group P″″ ofthe amino group of Compound HH. The reaction conditions at this time areappropriately selected depending on the kind of the protecting groupP″″.

Moreover, the present invention also relates to intermediate compoundsfor synthesizing a compound of the formula (I) that are represented bythe formula:

(wherein P and P′ may be the same or different and each represent ahydroxy protecting group) and the formula:

(wherein A, D, X and Y have the same meanings as defined).

These compounds can be produced in accordance with General ProductionMethod 1 that describes a method for producing a compound of theaforementioned formula (I).

The compound of the present invention can be used as a drug either assuch or in the form of a pharmacologically acceptable salt thereof.There are no particular restrictions on the salt as long as it ispharmacologically acceptable, and examples include salts of mineralacids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoricacid and hydrobromic acid; salts of organic acids such as acetic acid,tartaric acid, lactic acid, citric acid., fumaric acid, maleic acid,succinic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid,and camphorsulfonic acid; and salts of alkali metals or alkaline earthmetals such as sodium, potassium and calcium.

While the amount of the active ingredient compound contained in theaforementioned pharmaceutical composition is not subjected to anyparticular restrictions and is suitably selected over a wide range, itis, for example, 0.1 to 99.5% by weight, and preferably 0.5 to 90% byweight.

A compound of the present invention can be formulated using a knownauxiliary agent such as vehicle, binder, disintegrating agent,lubricant, flavoring agent, dissolving assistant, suspending agent andcoating agent which can be normally used in the formulation technologyfields of drugs. When forming into the form of tablets, a wide range ofknown carriers in the field can be used, examples of which includevehicles such as lactose, sucrose, sodium chloride, glucose, urea,starch, calcium carbonate, kaolin, crystalline cellulose and silicicacid; binders such as water, ethanol, propanol, simple syrup, liquidglucose, liquid starch, liquid gelatin, carboxymethyl cellulose,shellac, methyl cellulose, potassium phosphate and polyvinylpyrrolidone;disintegrating agents such as dry starch, sodium alginate, powderedagar, powdered laminaran, sodium hydrogencarbonate, calcium carbonate,polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate,monoglyceride stearate, starch and lactose; disintegration inhibitorssuch as sucrose, stearine, cocoa butter and hydrogenated oils;absorption promoters such as quaternary ammonium salts and sodium laurylsulfate; moisture retention agents such as glycerin and starch;adsorbents such as starch, lactose, kaolin, bentonite and colloidalsilicic acid; and lubricants such as refined talc, stearate salts,powdered boric acid and polyethylene glycol.

Moreover, tablets may be in the form of tablets provided with anordinary coating as necessary, examples of which include sugar-coatedtablets, gelatin-encapsulated tablets, enteric-coated tablets,film-coated tablets, or double-layer tablets and multi-layer tablets.When forming into the form of a pill, a wide range of materials can beused as the carrier that are conventionally known in the field, examplesof which include vehicles such as glucose, lactose, cocoa butter,starch, hardened vegetable oil, kaolin and talc; binders such as gumarabic powder, tragacanth powder, gelatin and ethanol; anddisintegration agents such as laminaran agar. When forming into the formof a suppository, a wide range of materials can be used as the carrierthat are conventionally known in the field, examples of which includepolyethylene glycol, cocoa butter, higher alcohols, esters of higheralcohols, gelatin and semi-synthetic glycerides. In the case ofpreparing in the form of an injection preparation, the solution andsuspension are preferably sterilized and made to be isotonic with blood,and when these are formed into the form of solutions, emulsions orsuspensions, all materials that are commonly used as diluents in thefield can be used, examples of which include water, ethanol, propyleneglycol, ethoxyisostearyl alcohol, polyoxyisostearyl alcohol andpolyoxyethylene sorbitan fatty acid esters. Furthermore, in this case,adequate amounts of salt, glucose or glycerin may be contained in thepharmaceutical preparation to prepare an isotonic solution, and ordinarydissolution assistants, buffers, analgesics and so forth may also beadded. Moreover, colorants, preservatives, fragrances, flavorings,sweeteners and other pharmaceuticals may also be contained as necessary.

The aforementioned pharmaceutical composition is preferably administeredin the unit dosage form, and can be administered by oral administration,tissue administration (subcutaneous administration, intramuscularadministration, intravenous administration, etc.), local administration(percutaneous administration, etc.) or administered rectally. Theaforementioned pharmaceutical composition is naturally administered in adosage form that is suitable for these administration methods.

In the case of administering a compound of the present invention or apharmaceutically acceptable salt thereof in the form of a drug, althoughpreferably adjusted in consideration of factors relating to patientstatus such as age and body weight, administration route, nature andseverity of the illness and so forth, the human adult dosage when usedas an antiviral drug is normally within the range of 0.1 to 2000 mg perday as the amount of active ingredient of the present invention.Although there are cases in which a dosage less than the aforementionedrange may still be adequate, there are also cases in which conversely adosage beyond the aforementioned range may be necessary. Whenadministering in large doses, it is preferable to administer by dividingthe dosage among several administrations per day.

The aforementioned oral administration can be performed in dose units ofa solid, powder or liquid, and can be performed in the form of a powder,granules, tablets, sugar-coated preparations, capsules, drops,sublingual preparations and other dosage forms.

The aforementioned tissue administration can be performed by using theliquid dose unit form for subcutaneous, intramuscular or intravenousinjection of a solution or suspension and so forth. These are producedby suspending or dissolving a fixed amount of a compound of the presentinvention or pharmaceutically acceptable salt thereof in a non-toxicliquid carrier compatible with the purpose of injection such as anaqueous or oily medium, followed by sterilization of the aforementionedsuspension or solution.

The aforementioned local administration (percutaneous administration,etc.) can be performed by using the form of an external preparation suchas a solution, cream, powder, paste, gel or ointment. These can beproduced by combining a fixed amount of a compound of the presentinvention or pharmaceutically acceptable salt thereof with one or moretypes of a fragrance, colorant, filler, surfactant, moisture retentionagent, skin softener, gelling agent, carrier, preservative or stabilizerand so forth that is applicable to the purpose of the externalpreparation.

The aforementioned rectal administration can be performed by using asuppository and so forth containing a fixed amount of a compound of thepresent invention or pharmaceutically acceptable salt thereof in a lowmelting point solid composed of, for example, a higher ester such aspalmitic myristyl ester, polyethylene glycol, cocoa butter or mixturethereof.

The aforementioned administration can be performed by using the liquiddose unit form for subcutaneous, intramuscular or intravenous injectionsuch as a solution or suspension and so forth. These are produced bysuspending or dissolving a fixed amount of a compound of the presentinvention or pharmaceutically acceptable salt thereof in a non-toxicliquid carrier applicable to the purpose of injection such as an aqueousor oily medium, followed by sterilization of the aforementionedsuspension or solution.

EXAMPLE

In the following, a preparation method of the compound of the formula(I) of the present invention and a pharmacological activity of thecompound of the formula (I) will be explained by Examples.

Example 1

1-1 (Step 1-1)

Compound 1 (70.1 g) as described in the above General Production Method1 was synthesized according to a method described in a literature (J.Org. Chem. 1989, 45, 5522, B. E. Marron, et al), a solution of thisCompound 1 in anhydrous diethyl ether (700 ml) was cooled to 0° C. andbis(2-methoxyethoxy) aluminum sodium hydride (414 mmol, 121 ml, 70%toluene solution) was slowly added thereto. An ice bath was removed in 5minutes after completion of addition of the reagent and stirringcontinued at room temperature for 1 hour. The reaction solution wascooled to 0° C. and anhydrous ethyl acetate (19.8 ml, 203 mmol) wasslowly added thereto. After the mixture was stirred at the sametemperature for 10 minutes, it was cooled to −78° C. and iodine (76.1 g,300 mmol) was added thereto. The temperature of the mixture wasgradually raised to room temperature over 2 hours to complete thereaction. An aqueous sodium hydrogensulfite solution was added to thereaction solution and ethyl acetate was added thereto. After thereaction solution was filtered by suction through celite, the organiclayer was separated and an aqueous layer was once again extracted withethyl acetate. After the combined organic layer was dried over anhydroussodium sulfate, it was concentrated under reduced pressure to obtaincrude title compound (100 g) as a light brown oil. The thus obtainedcrude product was used as such for the subsequent reaction.

Physicochemical properties of Compound 2

Molecular weight: 466

FAB-MS (positive mode, matrix m-NBA) 467 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.04 (9H, s),1.44 (1H, t, J=5 Hz), 2.73 (2H, t, J=6 Hz), 3.80 (2H, t, J=6 Hz), 4.18(2H, t, J=5 Hz), 5.91 (1H, t, J=5 Hz), 7.35-7.46 (6H, m), 7.65-7.69 (4H,m)1-2 (Step 1-2)

A solution of Compound 2 obtained in the above reaction indichloromethane (300 ml) was cooled to 0° C. and dihydropyran (22.7 ml,248 mmol) was added thereto. Pyridinium p-toluenesulfonate (260 mg, 1mmol) was added to the solution. After 1 hour, an aqueous sodiumbicarbonate solution was added thereto to stop the reaction. Theseparated organic layer was washed with saturated brine and after it wasdried over anhydrous sodium sulfate, it was concentrated under reducedpressure. The thus obtained crude compound 3 (108 g) was used as suchfor the subsequent reaction.

Physicochemical properties of Compound 3

Molecular weight: 550

FAB-MS (positive mode, matrix m-NBA) 551 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.04 (9H, s),1.49-1.91 (6H, m), 2.74 (2H, t, J=6 Hz), 3.46-3.58 (2H, m), 3.76 (2H, t,J=6 Hz), 3.82-3.93 (1H, m), 4.06 (1H, dd, J=13, 6 Hz), 4.27 (1H, dd,J=13, 6 Hz), 4.65 (1H, t, J=3 Hz), 5.91 (1H, t, J=5 Hz), 7.35-7.43 (6H,m), 7.65-7.69 (4H, m)1-3 (Step 1-3)

The crude Compound 3 (4.73 g) was dissolved in anhydrous diethyl ether(30 ml) and the solution was cooled to −78° C. tert-Butyllithium (17.2mmol, 10.7 ml, 1.6N pentane solution) was slowly added thereto. Afterthe mixture was stirred at the same temperature for 1 hour,paraformaldehyde (18.9 mmol, 570 mg) was added thereto. The mixture wasstirred at the same temperature for 30 minutes and the temperature ofthe mixture was raised to 0° C., followed by stirring of the mixture for1 hour. An aqueous ammonium chloride solution was added thereto to stopthe reaction and the reaction mixture was extracted with ethyl acetate.The aqueous layer was extracted with a small amount of ethyl acetate andthe combined organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The crude product obtained byconcentrating under reduced pressure was purified by columnchromatography (silica gel, hexane-ethyl acetate 9:1-4:1) to obtainCompound 4 (1.635 g) as a colorless oil.

Physicochemical properties of Compound 4

Molecular weight: 454

FAB-MS (positive mode, matrix m-NBA) 455 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.04 (9H, s),1.49-1.89 (6H, m), 2.41 (2H, t, J=6 Hz), 3.03 (1H, t, J=6 Hz), 3.47-3.58(2H, m), 3.75-3.92 (3H, m), 4.08-4.26 (4H, m), 4.68 (1H, t, J=3 Hz),5.53 (1H, t, J=7 Hz), 7.35-7.47 (6H, m), 7.64-7.68 (4H, m)1-4 (Step 1-4)

A solution of Compound 4 (344 mg, 0.76 mmol) and imidazole (77 mg, 1.14mmol) in anhydrous N,N-dimethylformamide (2 ml) was cooled to 0° C. andtert-butyldiphenylchlorosilane (0.2 ml, 0.76 mmol) was added thereto,followed by stirring of the mixture for 2 hours. An aqueous ammoniumchloride solution was added thereto to stop the reaction and thereaction mixture was extracted with hexane. The organic layer was washedtwice with water, subsequently with saturated brine and dried overanhydrous sodium sulfate, followed by concentration under reducedpressure to obtain the crude Compound 5 (554 mg) as a colorless oil.

Physicochemical properties of Compound 5

Molecular weight: 692

FAB-MS (positive mode, matrix m-NBA) 715 (M+Na⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.00 (9H, s),1.04 (9H, s), 1.38-1.82 (6H, m), 2.49 (2H, t, J=7 Hz), 3.29-3.42 (lH,m), 3.63-3.85 (4H, m), 4.00-4.09 (1H, m), 4.14 (2H, s), 4.46 (1H, t, J=3Hz), 5.43 (1H, t, J=7 Hz), 7.29-7.48 (12H, m), 7.57-7.78 (8H, m)1-5 (Step 1-5)

Pyridinium p-toluenesulfonate (90 mg, 0.36 mmol) was added to a solutionof Compound 5 (1.16 g, 1.67 mmol) in ethanol (6 ml) and the mixture wasstirred at 60° C. for 3.5 hours. After the solution was cooled to roomtemperature, a saturated aqueous sodium bicarbonate solution was addedthereto and the mixture was extracted with ethyl acetate. The organiclayer was successively washed with water and saturated brine and driedover anhydrous sodium sulfate, followed by concentration under reducedpressure. The thus obtained crude product was purified by columnchromatography (silica gel, hexane-ethyl acetate 20:1) to obtainCompound 6 (825 mg, 81%) as a colorless oil.

Physicochemical properties of Compound 6

Molecular weight: 608

FAB-MS (positive mode, matrix m-NBA) 631 (M+Na⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.01 (9H, s),1.01 (9H, s), 1.23 (1H, t, J=6 Hz), 2.41 (2H, t, J=7 Hz), 3.75 (2H, t,J=7 Hz), 3.90 (2H, t, J=6 Hz), 4.14 (2H, s), 5.47 (1H, t, J=7 Hz),7.29-7.47 (12H, m), 7.57-7.75 (8H, m)1-6 (step 1-6)

After a round-bottom flask with a rotor was heated and dried underreduced pressure, it was replaced with nitrogen and anhydrousdichloromethane (60 ml) was added thereto, followed by cooling to −20°C. Titanium tetra-isopropoxide (2.33 ml, 7.88 mmol) and L-(+)-diethyltartrate (1.62 ml, 9.46 mmol) were successively added thereto and afterthe mixture was stirred for 15 minutes, a solution of Compound 6 (4.80g, 7.88 mmol) in dichloromethane (30 ml) was added thereto, followed bystirring of the mixture for 15 minutes. The reaction mixture was cooledto −25° C. and tert-butylhydroperoxide (5.25 ml, 15.8 mmol, 3Ndichloromethane solution) was slowly added dropwise thereto. Aftercompletion of the dropwise addition, the mixture was stirred at −20° C.for 2 hours and dimethyl sulfide (1.1 ml) was added thereto, followed bystirring of the mixture at the same temperature for further 1 hour.After a 10% aqueous tartaric acid solution was added to the reactionsolution and the mixture was stirred for 30 minutes, the mixture wasstirred at room temperature for 1 hour. The organic layer was separated,the aqueous layer was extracted with a small amount of dichloromethaneand the combined organic layer was dried over anhydrous sodium sulfate.The crude product obtained by concentrating under reduced pressure waspurified by column chromatography (silica gel, hexane-ethyl acetate9:1). Compound 7 (4.78 g, 97%) was obtained as a colorless oil.Asymmetric yield (>95% ee) was determined by NMR analysis of thecorresponding MTPA ester.

Physicochemical properties of Compound 7

Molecular weight: 624

FAB-MS (positive mode, matrix m-NBA) 647 (M+Na⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.02 (9H, s),1.03 (9H, s), 1.72 (1H, t, J=6 Hz), 1.82 (1H, dt, J=14, 7 Hz), 2.23 (1H,dt, J=14, 6 Hz), 3.17 (1H, dd, J=6, 5 Hz), 3.55-3.79 (6H, m), 7.32-7.45(12H, m), 7.60-7.65 (8H, m)1-7 (Step 1-7)

Bis-cyclopentadienylzirconium hydrochloride (10.11 g, 37.2 mmol) wasadded to a solution of Compound 114 (10.45 g, 37.2 mmol) prepared inStep 2-3 of Preparation example 1 described below in anhydroustetrahydrofuran (100 ml) at room temperature under a nitrogen atmosphereand the mixture was stirred for 30 minutes. The thus obtained solutionwas cooled to −78° C. and methylmagnesium chloride (24.7 ml, 74 mmol, 3Ntetrahydrofuran solution) was added thereto, followed by stirring of themixture for 5 minutes. Copper (I) iodide (500 mg, 7.2 mmol) was added tothis solution and the temperature of the mixture was gradually raised to−30° C. A solution of Compound 7 (4.49 g) in anhydrous tetrahydrofuran(70 ml) was added thereto over 20 minutes and after completion of thedropwise addition, the mixture was stirred at −25° C. overnight. Asaturated aqueous ammonium chloride solution was slowly added thereto tostop the reaction and the temperature of the mixture was graduallyraised to room temperature. The mixture was stirred at room temperaturefor 10 hours and the resulting white solid was removed by filtrationthrough celite. Celite was sufficiently washed with ethyl acetate andthe organic layer was separated. The aqueous layer was extracted with asmall amount of ethyl acetate and the combined organic layer was washedwith a saturated aqueous ammonium chloride solution, followed by dryingover anhydrous sodium sulfate. The crude product obtained byconcentrating under reduced pressure was purified by columnchromatography (silica gel, hexane-ethyl acetate 20:1-9:1) to obtainCompound 8 (5.96 g, 91%) as a pale yellow oil.

Physicochemical properties of Compound 8

Molecular weight: 907

FAB-MS (negative mode, matrix m-NBA) 906 (M−H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 0.88 (3H, t, J=7Hz), 0.99 (9H, s), 1.04 (9H, s), 1.18-1.63 (22H, m), 1.78-2.01 (4H, m),2.44-2.57 (1H, m), 3.00 (1H, t, J=6 Hz), 3.59-3.92 (10H, m), 4.28 (1H,s), 5.37-5.55 (2H, m), 7.29-7.65 (20H, m)1-8 (Step 1-8)

Compound 8 (5.30 g, 5.84 mmol) was dissolved in dichloromethane (200 ml)and 2,2-dimethoxypropane (150 ml) and pyridinium p-toluenesulfonate (15mg, 0.058 mmol) was added thereto, followed by stirring of the mixtureat room temperature overnight. A saturated aqeuous sodium bicarbonatesolution was added thereto to stop the reaction and the reaction mixturewas extracted twice with dichloromethane. The extract was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thethus obtained crude product was purified by column chromatography(silica gel, hexane-ethyl acetate 20:1). Compound 9 (4.69 g, 86%) wasobtained as a pale yellow oil.

Physicochemical properties of Compound 9

Molecular weight: 947

FAB-MS (negative mode, matrix m-NBA) 946 (M−H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 0.88 (3H, t, J=6Hz), 1.02 (9H, s), 1.05 (9H, s), 1.14-1.63 (28H, m), 1.78-2.16 (4H, m),2.41-2.51 (1H, m), 3.47 (1H, d, J=10 Hz), 3.64-3.86 (6H, m), 3.92 (s,4H), 5.36-5.42 (2H, m), 7.28-7.47 (12H, m), 7.61-7.69 (8H, m)1-9 (Step 1-9)

A solution of Compound 9 (4.39 g, 4.64 mmol) in tetrahydrofuran (50 ml)was cooled to 0° C. and tetrabutyl ammonium fluoride (10.2 ml, 10.2mmol, 1M tetrahydrofuran solution) and acetic acid (0.53 ml, 9.27 mmol)were added thereto. The temperature of the mixture was gradually raisedto room temperature and the mixture was stirred for 2 days. A saturatedaqueous ammonium chloride solution was added thereto and the mixture wasextracted twice with dichloromethane. The combined organic layer waswashed with an aqueous sodium bicarbonate solution and dried overanhydrous sodium sulfate, followed by concentration under reducedpressure. The thus obtained crude product was purified by columnchromatography (silica gel, hexane-ethyl acetate 9:1-3:2) to obtainCompound 10 (1.73 g, 81%) as a pale yellow oil.

Physicochemical properties of Compound 10

Molecular weight: 470

FAB-MS (positive mode, matrix m-NBA) 493 (M+Na⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 0.88 (3H, t, J=6Hz), 1.17-1.73 (26H, m), 1.91-2.16 (4H, m), 2.44 (1H, brs), 2.73 (1H,dt, J=6, 10 Hz), 2.95 (1H, brs), 3.48 (1H, d, J=11 Hz), 3.63-4.01 (m,10H), 5.15 (1H, dd, J=15, 9 Hz), 5.55 (1H, dt, J=15, 7 Hz)1-10 (Step 1-10)

A solution of oxalyl chloride (0.575 ml, 6.6 mmol) in anhydrousdichloromethane (17 ml) was cooled to −78° C. under a nitrogenatmosphere and a solution of dimethyl sulfoxide (0.936 ml, 13.2 mmol) indichloromethane (1 ml) was added dropwise thereto, followed by stirringof the mixture for 15 minutes. A solution of Compound 10 (388 mg, 0.824mmol) in dichloromethane (5 ml) was slowly added dropwise thereto. Afterthe mixture was stirred at the same temperature for 1 hour,triethylamine (3 ml, 21.4 mmol) was added thereto and the mixture wasfurther stirred for 30 minutes. The cooling bath was removed and anitrogen stream was blown to the solution to remove the compound of lowboiling point, followed by drying under reduced pressure. Diethyl ether(15 ml) was added to the residue and the insolubles were removed byfiltration and the filtrate was concentrated. After this procedure wascarried out twice, the thus obtained residue was immediately used forthe subsequent reaction.

The above crude dialdehyde was dissolved in 2-methyl-2-propanol (24 ml)and 2-methyl-2-butene (6 ml) and. the mixture was cooled toapproximately 5 to 7° C. A solution of sodium chlorite (745 mg, 8.24mmol) and sodium dihydrogenphosphate (745 mg, 6.21 mmol) in water (7.45ml) was slowly added dropwise to this solution. After 2 hours, themixture was cooled to 0° C. and an aqueous sodium dihydrogenphosphatesolution was added thereto to adjust pH to approximately 5. The mixturewas extracted three times with dichloromethane and after the combinedorganic layer was washed with saturated brine, it was dried overanhydrous sodium sulfate. After filtration, the pale yellow oil residueobtained by concentration under reduced pressure was immediately usedfor the subsequent reaction without further purification.

The crude dicarboxylic acid was dissolved in N,N-dimethylformamidedi-tert-butylacetal (4.5 ml) and the mixture was stirred at 70° C. for 1hour. The compound of low boiling point was distilled off under reducedpressure. The residue was purified by column chromatography (silica gel,hexane-ethyl acetate 20:1) to obtain Compound 11 (340 mg, 60%) as a paleyellow oil.

Physicochemical properties of Compound 11

Molecular weight: 610

FAB-MS (positive mode, matrix m-NBA) (M+H⁺) 611, (M+Na⁺) 633

¹H-NMR (in deutero chloroform) chemical shift value δ: 0.88 (3H, t, J=6Hz), 1.18-1.64 (46H, m), 1.99 (2H, q, J=7 Hz), 2.69 (2H, ABq, J=15, 18Hz), 2.93 (1H, q, J=7 Hz), 3.82-3.88 (2H, m), 3.92 (4H, s), 5.51-5.69(2H, m)1-11 (Step 1-11)

Compound 11 (340 mg, 0.556 mmol) was dissolved in tetrahydrofuran (1 ml)and 80% aqueous acetic acid solution (10 ml) was added thereto, followedby stirring of the mixture at room temperature for 3.5 hours. After themixture was slowly added to a saturated aqueous sodium bicarbonatesolution to neutralize acetic acid, the mixture was extracted twice withethyl acetate. The extract was dried over anhydrous sodium sulfate,subsequently filtered and concentrated under reduced pressure to obtainCompound 12 (290 mg, 99%) as a pale yellow oil.

Physicochemical properties of Compound 12

Molecular weight: 526

FAB-MS (positive mode, matrix m-NBA) (M+H⁺) 527, (M+Na⁺) 549

¹H-NMR (in deutero chloroform) chemical shift value δ: 0.88 (3H, t, J=7Hz), 1.18-1.68 (36H, m), 2.01 (2H, q, J=7 Hz), 2.25-2.41 (5H, m), 1.99(1H, d, J=7 Hz), 2.04 (1H, d, J=7 Hz), 3.62-3.82 (2H, m), 3.99 (1H, s),5.42 (1H, dd, J=9, 15 Hz), 5.58 (1H, dt, J=16, 6 Hz)1-12 (Step 1-12)

Acetone (45 ml) was cooled to 0° C. and Jones reagent (0.48 ml, 0.9mmol, 1.89N) was added thereto. A solution of Compound 12 (216 mg, 0.41mmol) in acetone (3 ml) was slowly added dropwise to this mixture. Afterthe mixture was stirred at the same temperature for 1 hour, an aqueoussodium hydrogensulfite solution was added thereto to stop the reactionuntil yellow color of the reaction solution disappeared and a dark greenprecipitate appeared. Saturated brine (20 ml) was added thereto and themixture was extracted twice with dichloromethane. The combined organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (dichloromethane-methanol 50:1-20:1) to obtain Compound13 (198 mg, 89%) as a pale yellow oil.

Physicochemical properties of Compound 13

Molecular weight: 541

ESI (LC/MS positive mode) (M+H⁺) 542

¹H-NMR (in deutero chloroform) chemical shift value δ: 0.88 (3H, t, J=6Hz), 1.16-1.67 (36H, m), 1.99 (2H, q, J=6 Hz), 2.35 (4H, t, J=8 Hz),2.70 (1H, d, J=16 Hz), 2.90 (1H, d, J=16 Hz), 3.28 (1H, d, J=9 Hz), 5.52(1H, dd, J=9, 15 Hz), 5.68 (1H, dt, J=15, 5 Hz)1-13 (Step 1-13)

A solution of Compound 13 (6.0 mg, 0.011 mmol) and(S)-4-phenyloxyphenylalanine t-butylester hydrochloride (5 mg, 0.013mmol) in N,N-dimethylformamide (1 ml) was cooled to −10° C. andN,N-diisopropylethylamine (0.005 ml, 0.024 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (6.3 mg, 0.0166 mmol) were successively addedthereto. The temperature of the mixture was slowly raised to roomtemperature and the mixture was stirred overnight. An aqueous ammoniumchloride solution was added thereto to stop the reaction and thereaction mixture was extracted with ethyl acetate. The organic layer wassuccessively washed twice with water and then with saturated brine anddried over anhydrous sodium sulfate. After filtration and concentrationunder reduced pressure, the residue was purified by silica gel thinlayer chromatography (hexane-ethyl acetate 7:3) to obtain Compound 14(7.6 mg, 82%) as a colorless solid.

Physicochemical properties of Compound 14

Molecular weight: 835

ESI (LC/MS positive mode) 858 (M+Na⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 0.88 (3H, t, J=6Hz), 1.17-1.67 (45H, m), 1.97 (2H, q, J=7 Hz), 2.33-2.42 (4H, m), 2.58(1H, d, J=17 Hz), 2.76 (1H, d, J=17 Hz), 3.00-3.15 (3H, m), 4.23 (1H,s), 4.70 (1H, q, J=8 Hz), 5.47 (1H, dd, J=9, 15 Hz), 5.65 (1H, dt, J=15,7 Hz), 6.88-6.98 (2H, m), 7.01-7.12 (2H, m), 7.15-7.22 (2H, m),7.27-7.36 (2H, m)1-14 (Step 1-14)

A solution of Compound 14 (7.6 mg) in dichloromethane (3 ml) was cooledto 0° C. and anisole (0.01 ml) and trifluoroacetic acid (1 ml) weresuccessively added thereto. The temperature of the mixture was slowlyraised to room temperature and the mixture was stirred overnight. Afterthe reaction solution was concentrated under reduced pressure,azeotropic treatment was performed twice with benzene and the residuewas purified by Megabond elute diol (500 mg, Barian Inc.)(dichloromethane-methanol=20:1) to obtain Compound 15 (5.4 mg, 90%) as acolorless solid.

Physicochemical properties of Compound 15

Molecular weight: 667

ESI (LC/MS positive mode) 668 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7 Hz),1.14-1.38 (14H, m), 1.42-1.58 (4H, m), 1.89-2.01 (2H, m), 2.37-2.44 (4H,m), 2.62 (1H, d, J=16 Hz), 2.88-3.04 (2H, m), 3.20-3.30 (2H, m), 4.67(1H, dd, J=9, 5 Hz), 5.30-5.65 (2H, m), 6.87 (2H, d, J=9 Hz), 6.94 (2H,d, J=8 Hz), 7.08 (1H, t, J=8 Hz), 7.20 (2H, d, J=9 Hz), 7.33 (2H, t, J=8Hz)

The compounds of Example 2 to Example 97 described below can besynthesized from the corresponding compounds by a similar method to thatin the above Example 1. The corresponding compounds can be synthesizedby a person skilled in the art from the known compounds and thecompounds which can be easily synthesized from the known compounds by aperson skilled in the art.

Example 2

Physicochemical properties of Compound 16

Molecular weight: 589

ESI (LC/MS positive mode) 590 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=7 Hz),1.20-1.35 (14H, m), 1.46-1.58 (4H, m), 1.96 (2H, q, J=5.4 Hz), 2.27 (3H,s), 2.40-2.52 (5H, m), 2.84 (1H, d, J=16 Hz), 2.89 (1H, d, J=16 Hz),2.92 (1H, dd, J=14, 9 Hz), 3.04-3.25 (2H, m), 4.65 (1H, dd, J=9, 5 Hz),5.45-5.64 (2H, m), 7.03-7.12 (4H, m)

Example 3

Physicochemical properties of Compound 17

Molecular weight: 681

ESI (LC/MS positive mode) 682 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7 Hz),1.20-1.35 (14H, m), 1.41-1.59 (4H, m), 1.86-2.20 (2H, m), 2.30-2.48 (4H,m), 2.58 (1H, d, J=16 Hz), 2.78-2.90 (2H, m), 3.11-3.25 (2H, m), 4.64(1H, dd, J=9, 4 Hz), 5.43-5.60 (2H, m), 6.85-7.44 (9H, m)

Example 4

Physicochemical properties of Compound 18

Molecular weight: 643

ESI (LC/MS positive mode) 644 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=7 Hz),1.19-1.38 (14H, m), 1.42-1.60 (4H, m), 1.82 (3H, t, J=2 Hz), 1.89-2.02(2H, m), 2.44 (4H, t, J=7 Hz), 2.58 (1H, d, J=16 Hz), 2.78-2.98 (2H, m),3.09-3.23 (2H, m), 4.53-4.67 (3H, m), 5.39-5.61 (2H, m), 6.83 (2H, d,J=9 Hz), 7.13 (2H, d, J=9 Hz)

The above Compound 18 was synthesized by using Compound 18-4 in Step1-13 of General Production Method 1. Compound 18-4 was synthesized bythe following steps starting from Compound 18-1.Synthesis of Compound 18-4

a) Synthesis of Compound 18-2

After di-t-butyl dicarbonate (6.55 g, 30 mmol) was added to a suspension(44 ml) of L-tyrosine t-butylester (7.12 g, 30 mmol) in absolutemethanol, the mixture was stirred at room temperature for 2 hours. Afterthe reaction solution was concentrated, the thus obtained oil waspurified by silica gel column chromatography. Compound 18-2 (9.62 g,95%) was obtained as a colorless powder by treating the oil obtainedfrom the elution part of n-hexane/ethyl acetate (2:1→1:1) withn-hexane/ethyl acetate (10:1).

Physicochemical property of Compound 18-2

Molecular weight 337

ESI (LC/MS positive mode) 338 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.41 (9H, s),1.42 (9H, s), 2.90-3.01 (2H, m), 4.36-4.45 (1H, m), 5.01 (1H, d, J=7.5Hz), 5.67 (1H, s), 6.73 (2H, d, J=8.5 Hz), 7.01 (2H, d, J=8.5 Hz)b) Synthesis of Compound 18-3

Potassium carbonate (173 mg, 1.25 mM) and 1-bromo-2-butyne (147 mg, 1.1mmol) were added to a solution (2.0 ml) of the above Compound 18-2 (338mg, 1.0 mmol) in anhydrous N,N-dimethylformamide, and the mixture wasstirred at room temperature for 15 hours. Ethyl acetate (30 ml) wasadded to the reaction solution and the solution was subsequently washedthree times with water (20 ml) and then with saturated brine (20 ml).The ethyl acetate layer was dehydrated and dried with anhydrous sodiumsulfate and after the solvent was distilled off under reduced pressure,the thus obtained oil was purified by silica gel column chromatography.Compound 18-3 (370 mg, 95%) was obtained as a colorless oil from theelution part of n-hexane/ethyl acetate (5:1).

Physicochemical property of Compound 18-3

Molecular weight 389

FAB-MS (positive mode, Matrix m-NBA) 390 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.41 (9H, s),1.42 (9H, s), 1.86 (3H, t, J=2.5 Hz), 3.00 (2H, d, J=6.0 Hz), 4.41 (1H,dd, J=7.5, 6.0 Hz), 4.62 (2H, q, J=2.5 Hz), 4.97 (1H, d, J=7.5 Hz), 6.88(2H, d, J=8.5 Hz), 7.08 (2H, d, J=8.5 Hz)c) Synthesis of Compound 18-4

The thus obtained oil (390 mg, 1.0 mmol) was dissolved in ethyl acetate(5.0 ml), and 4N-hydrogenchloride in ethyl acetate (2.0 ml, 8.0 mmol)was added thereto, followed by stirring of the mixture at roomtemperature for 15 hours. The precipitated powder was collected byfiltration by Kiriyama funnel and washed with ethyl acetate (2.0 ml),followed by dried under reduced pressure by a vacuum pump to obtainCompound 18-4 (278 mg, 85%) as a colorless powder.

Physicochemical property of Compound 18-4

Molecular weight 289

ESI (LC/MS positive mode) 290 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 1.44 (9H, s), 1.80 (3H,t, J=2.5 Hz), 3.11 (2H, d, J=7.0 Hz), 4.12 (1H, t, J=7.0 Hz), 4.66 (2H,q, J=2.5 Hz), 6.96 (2H, d, J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz)

Example 5

Physicochemical properties of Compound 19

Molecular weight: 651

ESI (LC/MS positive mode) 652 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7 Hz),1.10-1.57 (18H, m), 1.82-1.98 (2H, m), 2.32-2.43 (4H, m), 2.63 (1H, d,J=16 Hz), 2.90 (1H, d, J=16 Hz), 3.04 (1H, dd, J=5, 9 Hz), 3.20-3.25(2H, m), 4.73 (1H, dd, J=9, 5 Hz), 5.40-5.62 (2H, m), 7.28-7.60 (9H, m)

Example 6

Physicochemical properties of Compound 20

Molecular weight: 625

ESI (LC/MS positive mode) 626 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7 Hz),1.01-1.37 (14H, m), 1.40-1.57 (4H, m), 1.67-1.80 (2H, m), 2.33-2.46 (4H,m), 2.60 (1H, d, J=16 Hz), 2.87 (1H, d, J=16 Hz), 3.06-3.22 (2H, m),3.41 (1H, dd, J=5, 14 Hz), 4.80 (1H, dd, J=9, 4 Hz), 5.30-5.48 (2H, m),7.35-7.45 (3H, m), 7.68 (1H, s), 7.75-7.80 (3H, s)

Example 7

Physicochemical properties of Compound 21

Molecular weight: 673

ESI (LC/MS positive mode) 674 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=7 Hz),1.19-1.62 (24H, m), 1.71-1.82 (2H, m), 1.89-2.01 (4H, m), 2.43 (4H, t,J=7 Hz), 2.61 (1H, d, J=16 Hz), 2.82-2.96 (2H, m), 3.09-3.27 (2H, m),4.16-4.28 (1H, m), 4.62 (1H, dd, J=9, 4 Hz), 5.42-5.60 (2H, m), 6.78(2H, d, J=9 Hz), 7.10 (2H, d, J=9 Hz)

Example 8

Physicochemical properties of Compound 22

Molecular weight: 659

ESI (LC/MS positive mode) 660 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.81-0.92 (9H, m),1.15-1.63 (23H, m), 1.88-2.01 (2H, m), 2.43 (4H, t, J=7 Hz), 2.48-2.62(3H, m), 2.79-2.98 (2H, m), 3.12-3.27 (2H, m), 4.65 (1H, dd, J=9.4 Hz),5.44-5.59 (2H, m), 7.06 (2H, d, J=8 Hz), 7.12 (2H, d, J=8 Hz)

Example 9

Physicochemical properties of Compound 23

Molecular weight: 635

ESI (LC/MS positive mode) 636 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.17-1.36 (14H, m), 1.45-1.60 (4H, m), 1.90-2.02 (2H, m), 2.41-2.45 (4H,m), 2.53 (1H, d, J=16.0 Hz), 2.87 (1H, d, J=16.0 Hz), 2.92 (1H, dd,J=8.8, 14.0 Hz), 3.16-3.20 (2H, m), 3.78 (3H, s), 3.80 (3H, s), 4.67(1H, dd, J=4.8, 9.2 Hz), 5.47-5.58 (2H, m), 6.75 (1H, m), 6.82-6.84 (2H,m)

Example 10

Physicochemical properties of Compound 24

Molecular weight: 701

ESI (LC/MS positive mode) 702 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.23-131 (14H, m), 1.48-1.54 (4H, m), 1.95 (2H, q, J=6.9 Hz), 2.38-2.43(4H, m), 2.60 (1H, d, J=16.0 Hz), 2.90 (1H, d, J=16.0 Hz), 2.96 (1H, dd,J=9.2, 14.4 Hz), 3.20 (1H, d, J=5.6 Hz), 3.21 (1H, dd, J=9.2, 14.4 Hz),4.67 (1H, dd, J=4.8, 9.2 Hz), 5.47-5.60 (2H, m), 6.89 (2H, d, J=6.4 Hz),6.91 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.32 (2H, d, J=6.4 Hz)

Example 11

Physicochemical properties of Compound 25

Molecular weight: 685

ESI (LC/MS positive mode) 686 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.19-1.37 (14H, m), 1.46-1.58 (4H, m), 1.88-2.00 (2H, m), 2.39-2.44 (4H,m), 2.59 (1H, d, J=16.0 Hz), 2.90 (1H, d, J=16.0 Hz), 2.95-2.98 (1H, m),3.19-3.24 (2H, m), 4.66 (1H, dd, J=4.4, 9.2 Hz), 5.51-5.58 (2H, m),6.84-6.87 (2H, m), 6.95-6.99 (2H, m), 7.05-7.10 (2H, m), 7.18-7.21 (2H,m)

Example 12

Physicochemical properties of Compound 26

Molecular weight: 645

ESI (LC/MS positive mode) 646 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (6H, t, J=6.8 Hz),1.20-1.39 (18H, m), 1.49-1.62 (6H, m), 1.95-1.98 (2H, m), 2.41-2.45 (4H,m), 2.55 (2H, t, J=7.8 Hz), 2.56 (1H, d, J=16 Hz), 2.87 (1H, d, J=16Hz), 2.95 (1H, dd, J=8.8, 14.0 Hz), 3.17-3.24 (2H, m), 4.66 (1H, dd,J=4.4, 8.8 Hz), 5.47-5.61 (2H, m), 7.06 (2H, d, J=8.4 Hz), 7.11 (2H, d,J=8.4 Hz)

Example 13

Physicochemical properties of Compound 27

Molecular weight: 652

ESI (LC/MS positive mode) 653 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.17-1.20 (4H, m), 1.23-1.35 (10H, m), 1.45-1.54 (4H, m), 1.93 (2H, q,J=6.4 Hz), 2.38-2.44 (4H, m), 2.47 (1H, d, J=16.0 Hz), 2.85 (1H, d,J=16.0 Hz), 3.07 (1H, dd, J=9.4, 14.0 Hz), 3.17 (1H, d, J=8.4 Hz), 3.35(1H, m), 4.78 (1H, dd, J=4.8, 9.2 Hz), 5.52-5.58 (2H, m), 7.45 (2H, d,J=8.2 Hz), 7.68 (2H, d, J=8.2 Hz), 7.89-7.93 (1H, m), 8.58-8.61 (1H, m),8.70 (1H, d, J=4.4 Hz), 9.01 (1H, d, J=1.6 Hz)

Example 14

Physicochemical properties of Compound 28

Molecular weight: 685

ESI (LC/MS positive mode) 686 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7 Hz),1.17-1.18 (4H, m), 1.20-1.36 (10H, m), 1.46-1.56 (4H, m), 1.92 (2H, q,J=6.4 Hz), 2.36-2.44 (4H, m), 2.61 (1H, d, J=17 Hz), 2.91 (1H, d, J=17Hz), 3.04 (1H, dd, J=8.8, 14.0 Hz), 3.19 (1H, d, J=8.4 Hz), 3.29 (1H,dd, J=8.8, 14 Hz), 4.75 (1H, dd, J=9.2 Hz), 5.49-5.60 (2H, m), 7.30 (2H,d, J=8.0 Hz), 7.40 (2H, d, J=8.0 Hz), 7.50 (2H, d, J=8.0 Hz), 7.55 (2H,d, J=8.0 Hz)

Example 15

Physicochemical properties of Compound 29

Molecular weight: 669

ESI (LC/MS positive mode) 670 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.10-1.19 (4H, m), 1.19-1.35 (10H, m), 1.38-1.54 (4H, m), 1.91 (2H, q,J=6.5 Hz), 2.35-2.43 (4H, m), 2.60 (1H, d, J=16.8 Hz), 2.90 (1H, d,J=16.0 Hz), 3.02 (1H, dd, J=9.6, 14.0 Hz), 3.27 (1H, d, J=5.2 Hz),3.30-3.33 (1H, m), 4.73 (1H, dd, J=4.8, 9.2 Hz), 5.49-5.54 (2H, m),7.12-7.17 (2H, m), 7.30 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.4 Hz),7.58-7.61 (2H, m)

Example 16

Physicochemical properties of Compound 30

Molecular weight: 687

ESI (LC/MS positive mode) 688 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.2 Hz),1.11-1.25 (4H, m), 1.25-1.35 (10H, m), 1.40-1.60 (4H, m), 1.93 (2H, q,J=6.7 Hz), 2.36-2.43 (4H, m), 2.61 (1H, d, J=16.0 Hz), 2.90 (1H, d,J=16.0 Hz), 3.04 (1H, dd, J=9.6, 14.0 Hz), 3.21 (1H, d, J=8.0 Hz),3.27-3.30 (1H, m), 4.74 (1H, dd, J=4.4, 9.2 Hz), 5.47-5.58 (2H, m),7.00-7.05 (2H, m), 7.31 (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.4 Hz),7.43-7.51 (1H, m)

Example 17

Physicochemical properties of Compound 31

Molecular weight: 657

ESI (LC/MS positive mode) 658 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.17-1.19 (4H, m), 1.20-1.34 (10H, m), 1.45-1.55 (4H, m), 1.91 (2H, q,J=6.4 Hz), 2.36-2.44 (4H, m), 2.63 (1H, d, J=16.8 Hz), 2.91 (1H, d,J=16.0 Hz), 3.00 (1H, dd, J=9.2, 14.4 Hz), 3.20 (1H, d, J=8.0 Hz), 3.26(1H, dd, J=9.2, 14.4 Hz), 4.73 (1H, dd, J=4.8, 9.2 Hz), 5.46-5.53 (2H,m), 7.25 (2H, d, J=8.4 Hz), 7.39-7.45 (2H, m), 7.53-7.55 (3H, m)

Example 18

Physicochemical properties of Compound 32 (diastereomer mixture)

Molecular weight: 643

ESI (LC/MS positive mode) 644 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.19-1.38 (14H, m), 1.46-1.59 (4H, m), 1.90-2.00 (2H, m), 2.38-2.47 (4H,m), 2.54-2.59 (1H, m), 2.75-2.91 (1H, m), 3.04-3.19 (2H, m), 3.31-3.37(1H, m), 4.72-4.76 (1H, m), 5.43-5.60 (2H, m), 7.41-7.44 (2H, m),7.54-7.59 (2H, m)

Example 19

Physicochemical properties of Compound 33

Molecular weight: 600

ESI (LC/MS positive mode) 601 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7 Hz),1.19-1.35 (14H, m), 1.48-1.58 (4H, m), 1.90-2.00 (2H, m), 2.42-2.45 (4H,m), 2.51 (1H, d, J=16 Hz), 2.87 (1H, d, J=16 Hz), 3.06 (1H, dd, J=9.6,14 Hz), 3.14 (1H, d, J=4.4 Hz), 3.33-3.37 (1H, m), 4.75 (1H, dd, J=4.8,9.6 Hz), 5.44-5.57 (2H, m), 7.42 (2H, d, J=8.0 Hz), 7.63 (2H, d, J=8.0Hz)

Example 20

Physicochemical properties of Compound 34

Molecular weight: 609

ESI (LC/MS positive mode) 610 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.91-0.98 (3H, m),1.17-1.40 (14H, m), 1.41-1.62 (4H, m), 1.85-2.03 (2H, m), 2.36-2.48 (4H,m), 2.51-2.62 (1H, m), 2.82-3.02 (2H, m), 3.12-3.28 (2H, m), 4.61-4.71(1H, m), 5.40-5.62 (2H, m), 7.12-7.30 (4H, m)

Example 21

Physicochemical properties of Compound 35 (diastereomer mixture)

Molecular weight: 620

ESI (LC/MS positive mode) 621 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.17-1.35 (14H, m), 1.44-1.58 (4H, m), 1.89-1.99 (2H, m), 2.36-2.49 (5H,m), 2.68-2.88 (1H, m), 3.08-3.16 (2H, m), 3.38-3.44 (1H, m), 4.77-4.83(1H, m), 5.46-5.58 (2H, m), 7.46-7.51 (2H, m), 8.12-8.18 (2H, m)

Example 22

Physicochemical properties of Compound 36

Physicochemical property

Molecular weight: 581

ESI (LC/MS positive mode) 582 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.25-1.43 (14H, m), 1.50-1.54 (4H, m), 2.00 (2H, q, J=6.4 Hz), 2.41-2.45(4H, m), 2.65 (1H, d, J=16.0 Hz), 2.86 (1H, d, J=16.0 Hz), 3.21 (1H, d,J=17.2 Hz), 3.27 (1H, dd, J=5.2, 14.8 Hz), 3.42 (1H, dd, J=5.2, 14.8Hz), 4.67 (1H, dd, J=5.2, 8.0 Hz), 5.53-5.66 (2H, m) 6.88-6.90 (2H, m),7.19-7.21 (1H, m)

Example 23

Physicochemical properties of Compound 37

Molecular weight: 631

ESI (LC/MS positive mode) 632 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.21-1.39 (23H, m), 1.48-1.58 (4H, m), 1.97 (2H, q, J=6.4 Hz), 2.41-2.45(4H, m), 2.59 (1H, d, J=16.4 Hz), 2.88 (1H, d, J=16.4 Hz), 2.96 (1H, dd,J=8.8, 14.4 Hz), 3.16-3.21 (2H, m), 4.65 (1H, dd, J=4.4, 8.8 Hz),5.49-5.64 (2H, m), 7.14 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz)

Example 24

Physicochemical properties of Compound 38

Molecular weight: 685

ESI (LC/MS positive mode) 686 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.2 Hz),1.07-1.19 (4H, m), 1.19-1.34 (10H, m), 1.45-1.55 (4H, m), 1.90 (2H, q,J=6.4 Hz), 2.33-2.43 (4H, m), 2.61 (1H, d, J=16.0 Hz), 2.91 (1H, d,J=16.0 Hz), 3.02 (1H, dd, J=10.0, 14.0 Hz), 3.19 (1H, d, J=8.0 Hz),3.27-3.31 (1H, m), 4.72-4.77 (1H, m), 5.44-5.55 (2H, m), 7.32 (3H, m),7.40 (1H, m), 7.52 (3H, m), 7.58 (1H, s)

Example 25

Physicochemical properties of Compound 39

Molecular weight: 701

ESI (LC/MS positive mode) 702 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.2 Hz),1.15-1.37 (14H, m), 1.41-1.58 (4H, m), 1.90-2.00 (2H, m), 2.41 (4H, q,J=7.2 Hz), 2.61 (1H, d, J=16.0 Hz), 2.92 (1H, d, J=16.4 Hz), 2.98 (1H,dd, J=9.6, 14.0 Hz), 3.21 (1H, d, J=8.8 Hz), 3.27 (1H, dd, J=9.6, 14.0Hz), 4.69 (1H, dd, J=5.2, 9.6 Hz), 5.46-5.63 (2H, m), 6.85-6.88 (1H, m),6.91-6.93 (3H, m), 7.06-7.09 (1H, m), 7.25 (2H, d, J=8.8 Hz), 7.30 (1H,m)

Example 26

Physicochemical properties of Compound 40

Molecular weight: 647

ESI (LC/MS positive mode) 648 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.80 (3H, t, J=7 Hz),0.98 (3H, t, J=7 Hz), 1.19-1.62 (20H, m), 1.91-2.03 (2H, m), 2.38-2.46(4H, m), 2.57 (1H, d, J=8 Hz), 2.84-2.96 (2H, m), 3.11-3.23 (2H, m),3.92 (2H, t, J=7 Hz), 4.63 (1H, dd, J=9, 5 Hz), 5.42-5.61 (2H, m), 6.80(2H, d, J=9 Hz), 7.11 (2H, d, J=9 Hz)

Example 27

Physicochemical properties of Compound 41

Molecular weight: 633

ESI (LC/MS positive mode) 634 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=7 Hz),1.03 (3H, t, J=7 Hz), 1.17-1.40 (14H, m), 1.43-1.60 (4H, m), 1.77 (2H,q, J=7 Hz), 1.91-2.01 (2H, m), 2.39-2.49 (4H, m), 2.56 (1H, d, J=17 Hz),2.80-2.97 (2H, m), 3.10-3.20 (2H, m), 3.88 (2H, t, J=7 Hz), 4.64 (1H,dd, J=9, 5 Hz), 5.42-5.61 (2H, m), 6.80 (2H, d, J=9 Hz), 7.12 (2H, d,J=9 Hz)

Example 28

Physicochemical properties of Compound 42

Molecular weight: 631

ESI (LC/MS positive mode) 632 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7 Hz),1.14-1.38 (14H, m), 1.42-1.58 (4H, m), 1.89-2.01 (2H, m), 2.37-2.46 (4H,m), 2.57 (1H, d, J=16 Hz), 2.82-2.96 (2H, m), 3.11-3.22 (2H, m),4.45-4.52 (2H, m), 4.63 (1H, dd, J=9, 4 Hz), 5.22 (1H, dd, J=10.1 Hz),5.37 (1H, dd, J=17.1 Hz), 5.45-5.59 (2H, m), 5.97-6.10 (1H, m), 6.82(2H, d, J=9 Hz), 7.14 (2H, d, J=9 Hz)

Example 29

Physicochemical properties of Compound 43

Molecular weight: 605

ESI (LC/MS positive mode) 606 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=7 Hz),1.18-1.40 (14H, m), 1.42-1.58 (4H, m), 1.91-2.01 (2H, m), 2.38-2.47 (4H,m), 2.53 (1H, d, J=15 Hz), 2.80-2.97 (2H, m), 3.11-3.21 (2H, m), 3.75(3H, s), 4.64 (1H, dd, J=9, 5 Hz), 5.44-5.62 (2H, m), 6.81 (2H, d, J=9Hz), 7.13 (2H, d, J=9 Hz)

Compounds 44 to 52 can be synthesized from Compound 8 in a similarmanner to Compound 15.

Example 30

Physicochemical properties of Compound 44

Molecular weight: 661

FAB-MS (positive mode, Matrix m-NBA) 662 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=7 Hz),0.96 (6H, d, J=6.5 Hz), 1.19-1.37 (14H, m), 1.46-1.58 (4H, m), 1.64 (2H,q, J=6.5 Hz), 1.74-1.89 (1H, m), 1.92-2.00 (2H, m), 2.43 (4H, t, J=7.5Hz), 2.59 (1H, d, J=16 Hz), 2.89 (1H, d, J=16 Hz), 2.92 (1H, dd, J=14, 9Hz), 3.16 (1H, dd, J=14, 4.5 Hz), 3.21 (1H, d, J=8 Hz), 3.95 (2H, t,J=6.5 Hz), 4.63 (1H, dd, J=9, 4.5 Hz), 5.44-5.61 (2H, m), 6.79 (2H, d,J=8.5 Hz), 7.11 (2H, d, J=8.5 Hz)

Example 31

Physicochemical properties of Compound 45

Molecular weight: 661

FAB-MS (positive mode, Matrix m-NBA) 662 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),0.96 (6H, d, J=6.5 Hz), 1.20-1.35 (14H, m), 1.45-1.57 (4H, m), 1.64 (2H,q, J=6.5 Hz), 1.74-1.89 (1H, m), 1.94-2.01 (2H, m), 2.39-2.45 (4H, m),2.59 (1H, d, J=16 Hz), 2.89 (1H, d, J=16 Hz), 2.90 (1H, dd, J=14, 9 Hz),3.16 (1H, dd, J=14, 4.5 Hz), 3.20 (1H, d, J=8.5 Hz), 3.96 (2H, t, J=6.5Hz), 4.64 (1H, dd, J=9, 4.5 Hz), 5.46-5.60 (2H, m), 6.79 (2H, d, J=8.5Hz), 7.11 (2H, d, J=8.5 Hz)

Example 32

Physicochemical properties of Compound 46

Molecular weight: 605

FAB-MS (positive mode, Matrix m-NBA) 606 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=7.5 Hz),0.96 (6H, d, J=6.5 Hz), 1.20-1.35 (6H, m), 1.47-1.58 (4H, m), 1.65 (2H,q, J=6.5 Hz), 1.74-1.89 (1H, m), 1.93-2.00 (2H, m), 2.42 (4H, t, J=7.5Hz), 2.59 (1H, d, J=16 Hz), 2.89 (1H, d, J=16 Hz), 2.90 (1H, dd, J=14, 9Hz), 3.16 (1H, dd, J=14, 4.5 Hz), 3.20 (1H, d, J=8.5 Hz), 3.95 (2H, t,J=6.5 Hz), 4.64 (1H, dd, J=9, 4.5 Hz), 5.45-5.61 (2H, m), 6.79 (2H, d,J=8.5 Hz), 7.11 (2H, d, J=8.5 Hz)

Example 33

Physicochemical properties of Compound 47

Molecular weight: 667

FAB-MS (positive mode, Matrix m-NBA) 668 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.96 (6H, d, J=6.5 Hz),1.18-1.36 (6H, m), 1.44-1.54 (2H, m), 1.63 (2H, q, J=6.5 Hz), 1.73-1.88(1H, m), 1.90-1.98 (2H, m), 2.39 (2H, t, J=7.5 Hz), 2.59 (1H, d, J=16Hz), 2.72-2.95 (6H, m), 3.15 (1H, dd, J=14, 4.5 Hz), 3.20 (1H, d, J=7.5Hz), 3.94 (2H, t, J=6.5 Hz), 4.63 (1H, dd, J=9, 4.5 Hz), 5.44-5.60 (2H,m), 6.79 (2H, d, J=8.5 Hz), 7.10 (2H, d, J=8.5 Hz), 7.14-7.27 (5H, m)

Example 34

Physicochemical properties of Compound 48

Molecular weight: 659

FAB-MS (positive mode, Matrix m-NBA) 660 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.96 (6H, d, J=6.5 Hz),1.21-1.42 (10H, m), 1.48-1.57 (4H, m), 1.64 (2H, q, J=6.5 Hz), 1.76-1.91(1H, m), 1.93-2.08 (4H, m), 2.40-2.46 (4H, m), 2.59 (1H, d, J=16 Hz),2.88 (1H, d, J=16 Hz), 2.90 (1H, dd, J=14, 9 Hz), 3.16 (1H, dd, J=14, 5Hz), 3.21 (1H, d, J=7.5 Hz), 3.95 (2H, t, J=6.5 Hz), 4.63 (1H, dd, J=9,5 Hz), 4.78-5.02 (2H, m), 5.45-5.60 (2H, m), 5.80 (1H, ddt, J=17, 10, 7Hz), 6.79 (2H, d, J=8.5 Hz), 7.11 (2H, d, J=8.5 Hz)

Example 35

Physicochemical properties of Compound 49

Molecular weight: 675

ESI (LC/MS positive mode) 676 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7 Hz),0.96 (6H, d, J=6.5 Hz), 1.17-1.40 (16H, m), 1.42-1.58 (4H, m), 1.64 (2H,q, J=6.5 Hz), 1.73-1.88 (1H, m), 1.89-2.03 (2H, m), 2.43 (4H, t, J=7.5Hz), 2.58 (1H, d, J=16 Hz), 2.89 (1H, d, J=16 Hz), 2.92 (1H, d, J=14Hz), 3.08-3.24 (2H, m), 3.95 (2H, t, J=6.5 Hz), 4.64 (1H, dd, J=8, 5.5Hz), 5.47-5.58 (2H, m), 6.79 (2H, d, J=8.5 Hz), 7.11 (2H, d, J=8.5 Hz)

Example 36

Physicochemical properties of Compound 50

Molecular weight: 661

ESI (LC/MS positive mode) 662 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.87 (6H, d, J=6.5 Hz),0.96 (6H, d, J=6.5 Hz), 1.08-1.42 (10H, m), 1.42-1.58 (5H, m), 1.64 (2H,q, J=6.5 Hz), 1.72-1.87 (1H, m), 1.89-2.04 (2H, m), 2.43 (4H, m), 2.58(1H, d, J=16 Hz), 2.89 (1H, d, J=16 Hz), 2.92 (1H, d, J=14 Hz),3.08-3.23 (2H, m), 3.95 (2H, t, J=6.5 Hz), 4.64 (1H, dd, J=9, 5 Hz),5.46-5.58 (2H, m), 6.79 (2H, d, J=8.5 Hz), 7.11 (2H, d, J=8.5 Hz)

Example 37

Physicochemical properties of Compound 51

Molecular weight: 647

FAB-MS (positive mode, Matrix m-NBA) 648 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=6.5 Hz),0.96 (6H, d, J=6.5 Hz), 1.20-1.37 (12H, m), 1.45-1.57 (4H, m), 1.64 (2H,q, J=6.5 Hz), 1.74-1.89 (1H, m), 1.93-2.00 (2H, m), 2.43 (4H, t, J=7Hz), 2.59 (1H, d, J=16 Hz), 2.89 (1H, d, J=16 Hz), 2.91 (1H, dd, J=14, 9Hz), 3.16 (1H, dd, J=14, 4.5 Hz), 3.20 (1H, d, J=6.5 Hz), 3.95 (2H, t,J=6.5 Hz), 4.63 (1H, dd, J=9, 4.5 Hz), 5.45-5.60 (2H, m), 6.79 (2H, d,J=8.5 Hz), 7.11 (2H, d, J=8.5 Hz)

Example 38

Physicochemical properties of Compound 52

Molecular weight: 673

ESI (LC/MS positive mode) 674 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.96 (6H, d, J=6.5 Hz),1.09-1.37 (11H, m), 1.37-1.58 (4H, m), 1.60-1.75 (8H, m), 1.75-1.90 (1H,m), 1.91-2.03 (2H, m), 2.43 (4H, m), 2.57 (1H, d, J=16 Hz), 2.88 (1H, d,J=16 Hz), 2.85-2.95 (1H, m), 3.10-3.24 (2H, m), 3.94 (2H, t, J=6.5 Hz),4.63 (1H, dd, J=5, 9 Hz), 5.44-5.60 (2H, m), 6.78 (2H, d, J=8.5 Hz),7.10 (2H, d, J=8.5 Hz)

Example 39

Physicochemical properties of Compound 53

Molecular weight: 681

ESI (LC/MS positive mode) 682 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7 Hz),1.18-1.36 (14H, m), 1.45-1.58 (4H, m), 1.93-1.98 (2H, m), 2.31 (3H, s),2.38-2.42 (4H, m), 2.61 (1H, d, J=16.0 Hz), 2.91 (1H, d, J=16.0 Hz),2.95 (1H, dd, J=9.2, 14.0 Hz), 3.18-3.23 (2H, m), 4.66 (1H, dd, J=9.2,4.4 Hz), 5.47-5.59 (2H, m), 6.81-6.86 (4H, m), 7.13-7.18 (4H, m)

The above Compound 53 was synthesized by using Compound 53-3 in Step1-13 of General Production Method-1 and Compound 53-3 was synthesized bythe following steps.Synthesis of Compound 53-3

a) Synthesis of Compound 53-1

Di-tert-butyl carbonate (24.4 ml, 106 mmol) was slowly added dropwise toa suspension of L-tyrosine-tert-butyl ester (25 g, 105 mmol) availableon market in methanol (150 ml). It was gradually dissolved with dropwiseaddition and the thus obtained solution was stirred for one hour. Afterthe reaction solution was concentrated, a mixture solution of hexane (90ml) and ethyl acetate (10 ml) was added to the thus obtained residue andpowdery precipitate was obtained by applying a ultrasonic waves thereto.The thus obtained powder is filtered by Kiriyama funnel to obtain 31.0 g(87.6%) of Compound 53-1 as a white powder.

Physicochemical properties of Compound 53-1

ESI (LC/MS positive mode) 338 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.41(9H,s),1.43(9H, s), 2.96-3.01 (2H, m), 4.37-4.42 (1H, m), 4.98-5.10 (1H, m),5.78 (1H, s) 6.70-6.75 (2H, m), 6.96-7.05 (2H, m)b) Synthesis of Compound 53-2

To Compound 53-1 (169 mg, 0.5 mmol) obtained by the above reaction in adichloromethane solvent (5.0 ml) of copper (II) diacetate (114 mg, 0.625mmol), 4-methylphenyl-boronic acid (175 mg, 1.25 mmol) and 4A-molecularsieves (500 mg), pyridine (0.2 ml, 2.5 mmol) was added dropwise,according to the method described in the literature (Tetrahedron Lett.,1998, 39, 2937). After 13 hours, the reaction solution was concentrated,ethyl acetate was added to the thus obtained residue and the insolubleswere filtered with Celite. The Celite was washed three times with ethylacetate and the filtrate was concentrated under reduced pressure. Thethus obtained crude product was purified by column chromatography(silica gel, hexane-ethyl acetate 5:1) to obtain Compound 53-2 (210 mg,98%) as a colorless oil.

Physicochemical property of Compound 53-2

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.41 (9H, s),1.43 (9H, s), 2.33 (3H, s), 2.92-3.09 (2H, m), 4.36-4.48 (2H, m)4.94-5.06 (2H, m), 6.83-6.94 (4H, m), 7.18-7.28 (4H, m)c) Synthesis of Compound 53-3

Compound 53-2 (204 mg, 0.48 mmol) obtained as mentioned above wasdissolved in anhydrous ethyl acetate (2.5 ml) and 4N-hydrogenchloride inethyl acetate (0.96 ml, 3.84 mmol) was slowly added dropwise thereto atroom temperature. After the mixture was stirred at room temperature for17 hours, the produced white precipitate was collected by filtrationwith Kiriyama funnel and washed with ethyl acetate. The thus obtainedproduct was dried under reduced pressure to obtain Compound 53-3 (127mg, 73%) as a white powder.

Physicochemical property of Compound 53-3

ESI (LC/MS positive mode) 328 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.43 (9H, s),2.32 (3H, s), 3.12-3.18 (2H, m), 4.15 (1H, t, J=7.1 Hz) 6.84-6.89 (2H,m) 6.90-6.98 (2H, m), 7.14-7.19 (2H, m)>7.22-7.27 (2H, m)

Example 40

Physicochemical properties of Compound 54

Molecular weight: 697

ESI (LC/MS positive mode) 698 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.17-1.36 (14H, m), 1.44-1.56 (4H, m), 1.88-1.99 (2H, m), 2.39-2.43 (4H,m), 2.60 (1H, d, J=16.0 Hz),2.90 (1H, d, J=16.0 Hz), 2.91-2.96 (1H, m),3.17-3.22 (2H, m),3.78 (3H, s), 4.65 (1H, dd, J=9.0, 4.6 Hz), 5.47-5.61(2H, m),6.78-6.81 (2H, m), 6.89-6.93 (4H, m), 7.13-7.16 (2H, m)

Example 41

Physicochemical properties of Compound 55

Molecular weight: 735

ESI (LC/MS positive mode) 736 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.18-1.36 (14H, m), 1.43-1.58 (4H, m), 1.90-2.00 (2H, m), 2.38-2.43 (4H,m), 2.61 (1H, d, J=16.0 Hz), 2.91 (1H, d, J=16.0 Hz), 2.99 (1H, dd,J=14.0, 9.6 Hz), 3.21 (1H, d, J=8.8 Hz), 3.26 (1H, dd, J=14.0, 4.6 Hz),4.70 (1H, dd, J=9.6, 4.6 Hz), 5.48-5.62 (2H, m), 6.95-6.99 (2H, m), 7.06(2H, d, J=8.2 Hz), 7.27-7.29 (2H, m), 7.62 (2H, d, J=8.2 Hz)

Example 42

Physicochemical properties of Compound 56

Molecular weight: 681

ESI (LC/MS positive mode) 682 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.2 Hz),1.18-1.34 (14H, m), 1.42-1.58 (4H, m), 1.90-1.99 (2H, m), 2.30 (3H, s),2.35-2.43 (4H, m), 2.62 (1H, d, J=14.0 Hz), 2.91 (1H, d, J=14.0 Hz),2.96 (1H, dd, J=12.8, 8.5 Hz), 3.19-3.24 (2H, m), 4.66 (1H, dd, J=4.8,8.5 Hz), 5.48-5.60 (2H, m), 6.72-6.78 (1H, m), 6.74-6.78 (1H, m),6.84-6.86 (2H, m), 6.90-6.92 (1H, m), 7.18-7.21 (3H, m)

Example 43

Physicochemical properties of Compound 57

Molecular weight: 735

ESI (LC/MS positive mode) 736 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.16-1.34 (14H, m), 1.42-1.58 (4H, m), 1.89-1.99 (2H, m), 2.34-2.43 (4H,m), 2.60 (1H, d, J=16.0 Hz), 2.91 (1H, d, J=16.0 Hz), 2.99 (1H, dd,J=14.0, 9.2 Hz), 3.21 (1H, d, J=8.4 Hz), 3.26 (1H, dd, J=4.8, 14.0 Hz),4.69 (1H, dd, J=9.2, 4.8 Hz), 5.49-5.60 (2H, m), 6.93-6.96 (2H, m),7.16-7.20 (2H, m), 7.26-7.28 (2H, m), 7.36-7.38 (1H, m), 7.50-7.54 (1H,m)

Example 44

Physicochemical properties of Compound 58

Molecular weight: 681

ESI (LC/MS positive mode) 682 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.09-1.34 (14H, m), 1.38-1.55 (4H, m), 1.84-1.92 (2H, m), 2.27-2.42 (4H,m), 2.63 (1H, d, J=16.0 Hz), 2.91 (1H, d, J=16.0 Hz), 3.00 (1H, dd,J=9.6, 14.0 Hz), 3.20 (1H, d, J=8.0 Hz), 3.27 (1H, dd, J=4.4, 14.0 Hz),3.81 (3H,s), 4.72 (1H, dd, J=9.6, 4.4 Hz), 5.48-5.52 (2H, m), 6.96-6.98(2H, m), 7.26 (2H, d, J=8.2 Hz), 7.47 (2H, d, J=8.2 Hz), 7.50-7.52 (2H,m)

Example 45

Physicochemical properties of Compound 59

Molecular weight: 665

ESI (LC/MS positive mode) 666 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.09-1.19 (4H, m), 1.21-1.35 (10H, m), 1.38-1.58 (4H, m), 1.86-1.94 (2H,m), 2.30-2.42 (7H, m), 2.63 (1H, d, J=16.0 Hz), 2.91 (1H, d, J=16.0 Hz),3.00 (1H, dd, J=9.6, 14.0 Hz), 3.20 (1H, d, J=8.4 Hz), 3.25-3.28 (1H,m), 4.72 (1H, dd, J=9.6, 4.8 Hz), 5.45-5.53 (2H, m), 7.22 (2H, d, J=8.0Hz), 7.27 (2H, d, J=8.0 Hz), 7.46-7.50 (4H, m)

Example 46

Physicochemical properties of Compound 60

Molecular weight: 719

ESI (LC/MS positive mode) 720 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.09-1.19 (4H, m), 1.19-1.33 (10H, m), 1.38-1.57 (4H, m), 1.85-1.94 (2H,m), 2.30-2.42 (4H, m), 2.58 (1H, d, J=16.0 Hz), 2.89 (1H, d, J=16.0 Hz),3.04 (1H, dd, J=14.2, 9.6 Hz), 3.19 (1H, d, J=8.4 Hz), 3.30-3.34 (1H,m), 4.75 (1H, dd, J=9.6, 4.6 Hz), 5.46-5.57 (2H, m), 7.36 (2H, d, J=8.4Hz), 7.60 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz), 7.79 (2H, d, J=8.4Hz)

Example 47

Physicochemical properties of Compound 61

Molecular weight: 665

ESI (LC/MS positive mode) 666 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.09-1.20 (4H, m), 1.20-1.34 (10H, m), 1.38-1.56 (4H, m), 1.85-1.93 (2H,m), 2.32-2.42 (7H, m), 2.64 (1H, d, J=16.0 Hz), 2.92 (1H, d, J=16.0 Hz),3.01 (1H, dd, J=9.6, 14.0 Hz), 3.21 (1H, d, J=8.0 Hz), 3.26-3.30 (1H,m), 4.73 (1H, dd, J=9.6, 4.6 Hz), 5.45-5.53 (2H, m), 7.12-7.14 (1H, m),7.26-7.30 (3H, m), 7.35-7.40 (2H, m), 7.49-7.51 (2H, m)

Example 48

Physicochemical properties of Compound 62

Molecular weight: 681

ESI (LC/MS positive mode) 682 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.08-1.20 (4H, m), 1.20-1.34 (10H, m), 1.38-1.58 (4H, m), 1.84-1.93 (2H,m), 2.39-2.42 (4H, m), 2.63 (1H, d, J=16.4 Hz), 2.91 (1H, d, J=16.4 Hz),3.01 (1H, dd, J=9.4, 13.8 Hz), 3.20 (1H, d, J=8.0 Hz), 3.27-3.31 (1H,m), 3.83 (3H, s), 4.73 (1H, dd, J=4.8, 9.4 Hz), 5.48-5.53 (2H, m),6.87-6.89 (1H, m), 7.10-7.13 (2H, m), 7.14-7.34 (3H, m), 7.50-7.52 (2H,m)

The above Compound 62 was synthesized by using Compound 62-6 in Step1-13 of General Production Method 1. Compound 62-6 was synthesized bythe following steps starting from Compound 62-1.Synthesis of Compound 62-6

a) Synthesis of Compound 62-2

Triethylamine (32.3 ml, 232 mmol) andN-(benzyloxycarbonyloxy)succinimide (57.8 g, 232 mmol) were added to asuspension (2.5 1) of L-tyrosine t-butyl ester (50.0 g, 211 mmol) inanhydrous dichloromethane and the mixture was stirred at roomtemperature for 20 hours. The reaction solution was subsequently washedwith a saturated aqueous ammonium chloride solution (1.5 l), a saturatedaqueous sodium bicarbonate solution (1.5 l) and saturated brine (2.0 l).After the organic layer was dehydrated and dried with anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure to obtainthe Compound 62-2 (82.5 g) as a colorless oil.

Physicochemical property of Compound 62-2

Molecular weight 371

ESI (LC/MS positive mode) 372 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.41 (9H, s),2.86-3.10 (2H, m), 4.36-4.56 (1H, m), 5.06 (1H, d, J=12.5 Hz), 5.11 (1H,d, J=12.5 Hz), 5.26-5.31 (1H, m), 6.00 (1H, brs), 6.69 (2H, d, J=8.5Hz), 6.98 (2H, d, J=8.5 Hz), 7.25-7.43 (5H, m)b) Synthesis of Compound 62-3

Anhydrous pyridine (88.5 ml, 1.09 mol) was added to a solution (400 ml)of Compound 62-2 (81.3 g) in anhydrous dichloromethane and the mixturewas cooled to 0-5° C. Then, trifluoromethanesulfonic anhydride (43.0 ml,262 mmol) was added dropwise thereto and the mixture was stirred at thesame temperature for 2 hours. Water (800 ml) and dichloromethane (1 1)were added to the reaction solution and the organic layer wassubsequently washed with a 0.5N aqueous-sodium hydroxide solution (650ml), water (800 ml), 1N hydrochloric acid (2×1 l) and water (1 l). Theorganic layer was dried with anhydrous sodium sulfate and concentratedto obtain Compound 62-3 (105.9 g) as a milky white solid.

Physicochemical property of Compound 62-3

Molecular weight 503

ESI (LC/MS positive mode) 504 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.37 (9H, s),3.10 (2H, d, J=6.5 Hz), 4.52 (1H, dt, J=7.5, 6.5 Hz), 5.07 (1H, d,J=12.5 Hz), 5.12 (1H, d, J=12.5 Hz), 5.30 (1H, d, J=7.5 Hz), 7.16 (2H,d, J=9.0 Hz), 7.23 (2H, d, J=9.0 Hz), 7.30-7.43 (5H, m)c) Synthesis of Compound 62-4

Compound 62-3 (5.0 g), 3-methoxyphenylboronic acid (2.57 g, 16.9 mmol)and potassium carbonate (2.33 g, 16.9 ml) were suspended in anhydroustoluene (100 ml) and tetrakis(triphenylphosphine) palladium(276 mg,0.239 mmol) was added thereto under an atmosphere of nitrogen. After themixture was stirred at 90° C. for 17 hours under a nitrogen stream, thereaction mixture was filtered by Celite and the residue was washed withethyl acetate (150 ml). The filtrate was subsequently washed with 0.5Naqueous sodium hydroxide solution (150 ml), water (150 ml), 1Nhydrochloric acid (150 ml), water (150 ml) and saturated brine (150 ml).The organic layer was dried with anhydrous sodium sulfate andconcentrated to obtain the crude Compound 62-4 (5.62 g) as a pale brownoil.

Physicochemical property of Compound 62-4

Molecular weight 461

ESI (LC/MS positive mode) 462 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.41 (9H, s),3.12 (2H, d, J=6.0 Hz), 3.85 (3H, s), 4.57 (1H, dt, J=8.0, 6.0 Hz), 5.08(1H, d, J=12.5 Hz), 5.13 (1H, d, J=12.5 Hz), 5.31 (1H, d, J=8.0 Hz),6.86-6.91 (1H, m), 7.09-7.51 (12H, m)d) Synthesis of Compound 62-5

A 10% palladium carbon catalyst (700 mg) was added to a solution (100ml) of Compound 62-4 (5.52 g) in methanol and the mixture was stirred atroom temperature for 2 days under a hydrogen (balloon) stream. Thereaction mixture was filtered through Celite and the residue was washedwith methanol (30 ml). The oil obtained by concentrating the filtratewas dissolved in ethyl acetate (100 ml) and subsequently extracted withlN hydrochloric acid (100 ml), water (100 ml) and 0.1N hydrochloric acid(100 ml). The aqueous layer and 0.1N hydrochloric acid layer werecombined and the pH was adjusted to 8.0 with a saturated aqueous sodiumhydrogencarbonate solution. The solution was extracted with ethylacetate (100 ml) and after the organic layer was washed with water (50ml), it was dried with anhydrous sodium sulfate and concentrated toobtain Compound 62-5 (2.43 g) as a colorless oil.

Physicochemical property of Compound 62-5

Molecular weight 327

ESI (LC/MS positive mode) 328 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.44 (9H, s),2.88 (1H, dd, J=13.5, 8.0 Hz), 3.08 (1H, dd, J=13.5, 5.5 Hz), 3.64 (1H,dd, J=8.0, 5.5 Hz), 3.86 (3H, s), 6.89 (1H, ddd, J=8.0, 2.5, 1.0 Hz),7.11 (1H, dd, J=2.5, 1.5 Hz), 7.17 (1H, ddd, J=8.0, 1.5, 1.0 Hz), 7.29(2H, d, J=8.5 Hz), 7.35 (1H, t, J=8.0 Hz), 7.35 (2H, d, J=8.5 Hz)e) Synthesis of Compound 62-6

A solution (100 ml) of Compound 62-5 (2.43 g) in ethyl acetate wascooled to 0-5° C. and 4N-hydrogenchloride in ethyl acetate (2.80 ml,11.2 mmol) was added thereto, followed by stirring of the mixture at thesame temperature for 1 hour. The precipitated powder was collected byfiltration by a Millipore filter (FR-20) and after it was washed withethyl acetate (20 ml), it was dried under reduced pressure by a vacuumpump to obtain Compound 62-6 (2.6 g) as a colorless powder.

Physicochemical property of Compound 62-6

Molecular weight 327

ESI (LC/MS positive mode) 328 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 1.45 (9H, s), 3.22 (2H,d, J=7.0 Hz), 3.84 (3H, s), 4.21 (1H, t, J=7.0 Hz), 6.92 (1H, ddd,J=8.0, 2.5, 1.0 Hz), 7.14 (1H, dd, J=2.5, 1.5 Hz), 7.19 (1H, ddd, J=8.0,1.5, 1.0 Hz), 7.35 (1H, t, J=8.0 Hz), 7.37 (2H, d, J=8.5 Hz), 7.63 (2H,d, J=8.5 Hz)

Example 49

Physicochemical property of Compound 63

Molecular weight 719

ESI (LC/MS positive mode) 720 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.08-1.20 (4H, m), 1.20-1.34 (10H, m), 1.38-1.58 (4H, m), 1.86-1.92 (2H,m), 2.32-2.42 (4H, m), 2.61 (1H, d, J=16.0 Hz), 2.90 (1H, d, J=16.0 Hz),3.04 (1H, dd, J=9.4, 14.2 Hz), 3.20 (1H, d, J=8.0 Hz), 3.30-3.31 (1H,m),4.75 (1H, dd, J=4.6, 9.4 Hz), 5.45-5.53 (2H, m), 7.36 (2H, d, J=8.4 Hz),7.57 (2H, d, J=8.4 Hz), 7.62-7.63 (2H, m), 7.85-7.87 (2H,m)

Example 50

Physicochemical property of Compound 64

Molecular weight 685

ESI (LC/MS positive mode) 686 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.6 Hz),1.15-1.37 (14H, m), 1.42-1.57 (4H, m), 1.89-1.99 (2H, m), 2.33-2.43 (4H,m), 2.61 (1H, d, J=16.0 Hz), 2.92 (1H, d, J=16.0 Hz), 2.98 (1H, dd,J=9.2, 14.0 Hz), 3.20-3.27 (2H,m), 4.68 (1H, dd, J=4.4, 9.2 Hz),5.52-5.58 (2H, m), 6.65-6.68 (1H, m), 6.73-6.76 (1H, m), 6.78-6.83 (1H,m), 6.93 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz), 7.29-7.34 (1H, m)

Example 51

Physicochemical property of Compound 65

Molecular weight 669

ESI (LC/MS positive mode) 670 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.10-1.22 (4H, m), 1.22-1.32 (10H, m), 1.38-1.58 (4H, m), 1.87-1.96 (2H,m), 2.32-2.42 (4H, m), 2.64 (1H, d, J=16.0 Hz), 2.92 (1H, d, J=16.0 Hz),3.04 (1H, dd, J=9.4, 13.6 Hz), 3.22 (1H, d, J=8.0 Hz), 3.27-3.30 (1H,m), 4.73 (1H, dd, J=4.6, 9.4 Hz), 5.51-5.56 (2H, m), 7.13-7.25 (2H, m),7.30-7.34 (3H, m), 7.43-7.47 (3H, m)

Example 52

Physicochemical property of Compound 66

Molecular weight 669

ESI (LC/MS positive mode) 670 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.2 Hz),1.08-1.20 (4H, m), 1.20-1.34 (10H, m), 1.40-1.58 (4H, m), 1.85-1.93 (2H,m), 2.32-2.42 (4H, m), 2.61 (1H, d, J=16.4 Hz), 2.90 (1H, d, J=16.4 Hz),3.02 (1H, dd, J=9.4, 13.8 Hz), 3.20 (1H,d,J=8.0 Hz), 3.27-3.30 (1H, m),4.74 (1H, dd, J=4.8, 9.4 Hz), 5.45-5.55 (2H, m), 7.02-7.07 (1H, m),7.31-7.33 (3H, m), 7.41-7.44 (2H, m), 7.53-7.55 (2H, m)

Example 53

Physicochemical property of Compound 67

Molecular weight 710

ESI (LC/MS positive mode) 711 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.18-1.37 (14H, m), 1.43-1.58 (4H, m), 1.90-1.99 (2H, m), 2.32-2.42 (4H,m), 2.60 (1H, d, J=16.0 Hz), 2.91 (1H, d, J=16.0 Hz), 2.95-3.15 (1H, m),3.20 (6H, s), 3.22-3.30 (2H, m), 4.68 (1H, dd, J=4.4, 9.2 Hz), 5.47-5.61(2H, m), 6.88-6.90 (2H, m), 7.01-7.05 (2H, m), 7.23 (2H, d, J=8.6 Hz),7.33 (2H, d, J=8.6 Hz)

Example 54

Physicochemical property of Compound 68

Molecular weight 694

ESI (LC/MS positive mode) 695 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.11-1.20 (4H, m), 1.20-1.35 (10H, m), 1.38-1.58 (4H, m), 1.85-1.94 (2H,m), 2.30-2.42 (4H, m), 2.62 (1H, d, J=16.0 Hz), 2.91 (1H, d, J=16.0 Hz),3.00 (1H, dd, J=9.6, 14.0 Hz), 3.13 (6H,s), 3.21 (1H,d, J=8.4 Hz),3.26-3.30 (1H, m), 4.73 (1H, dd, J=4.4, 9.6 Hz), 5.45-5.56 (2H, m), 7.21(2H, d, J=8.8 Hz), 7.28 (2H, d, J=8.2 Hz), 7.51 (2H, d, J=8.2 Hz), 7.62(2H, d, J=8.8 Hz)

Example 55

Physicochemical property of Compound 69

Molecular weight 666

ESI (LC/MS positive mode) 667 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.12-1.22 (4H, m), 1.22-1.35 (10H, m), 1.40-1.58 (4H, m), 1.90-2.00 (2H,m), 2.31-2.42 (4H, m), 2.65 (1H, d, J=16.4 Hz), 2.90-2.95 (2H, m),3.13-3.16 (1H, m), 3.23 (1H,d, J=8.0 Hz), 4.64 (1H, dd, J=4.6, 9.0 Hz),5.52-5.56 (2H, m), 6.78-6.82 (1H, m), 6.97-7.00 (2H, m), 7.02-7.08 (4H,m), 7.16-7.20 (2H, m)

Example 56

Physicochemical property of Compound 70

Molecular weight 692

ESI (LC/MS positive mode) 693 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.2 Hz),1.16-1.35 (14H, m), 1.44-1.58 (4H, m), 1.87-1.99 (2H, m), 2.34-2.45 (4H,m), 2.60 (1H, d, J=16.0 Hz), 2.91 (1H, d, J=16.0 Hz), 3.00 (1H, dd,J=9.4, 13.8 Hz), 3.21 (1H,d, J=8.8 Hz), 3.25-3.31 (1H, m), 4.70 (1H, dd,J=4.4, 9.4 Hz), 5.51-5.59 (2H, m), 6.99 (2H, d, J=8.8 Hz), 7.03 (2H, d,J=8.8 Hz), 7.30 (2H, d, J=8.8 Hz), 7.69 (2H, d, J=8.8 Hz)

Example 57

Physicochemical property of Compound 71

Molecular weight 676

ESI (LC/MS positive mode) 677 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.2 Hz),1.08-1.20 (4H, m), 1.20-1.35 (10H, m), 1.40-1.58 (4H, m), 1.84-1.92 (2H,m), 2.32-2.44 (4H, m), 2.56 (1H, d, J=16.0 Hz), 2.88 (1H, d, J=16.0 Hz),3.04 (1H, dd, J=9.4, 13.8 Hz), 3.18 (1H, d, J=8.4 Hz), 3.31-3.34 (1H,m), 4.75 (1H, dd, J=4.8, 9.4 Hz), 5.45-5.53 (2H, m), 7.36 (2H, d, J=8.4Hz), 7.60 (2H, d, J=8.4 Hz), 7.79-7.81 (4H, m)

Example 58

Physicochemical property of Compound 72

Molecular weight 660

ESI (LC/MS positive mode) 661 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.18-1.39 (14H, m), 1.45-1.51 (4H, m), 1.92-2.06 (2H, m), 2.38-2.49 (4H,m), 2.53 (1H, d, J=16.0 Hz), 2.86 (1H, d, J=16.0 Hz), 2.94 (1H, dd,J=8.8, 14.0 Hz), 3.17-3.23 (6H, m), 3.85-3.87 (4H, m), 4.65 (1H, dd,J=4.6, 8.8 Hz), 5.49-5.62 (2H, m), 7.02 (2H, d, J=8.8 Hz), 7.20 (2H, d,J=8.8 Hz)

Example 59

Physicochemical property of Compound 73

Molecular weight 682

ESI (LC/MS positive mode) 683 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.12-1.20 (4H, m), 1.20-1.38 (10H, m), 1.42-1.58 (4H, m), 1.86-1.95 (2H,m), 2.32-2.43 (4H, m), 2.58 (1H, d, J=16.0 Hz), 2.89 (1H, d, J=16.0 Hz),3.02 (1H, dd, J=9.2, 14.4 Hz), 3.19 (1H, d, J=8.0 Hz), 3.27-3.31 (1H,m), 3.94 (3H,s), 4.74 (1H, dd, J=4.8, 9.2 Hz), 5.46-5.56 (2H, m), 6.87(1H, d, J=8.6 Hz), 7.32 (2H, d, J=8.2 Hz), 7.49 (2H, d, J=8.2 Hz), 7.92(1H, dd, J=2.4, 8.6 Hz), 8.34 (1H, d, J=2.4 Hz)

Example 60

Physicochemical property of Compound 74

Molecular weight 758

ESI (LC/MS positive mode) 759 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.10-1.20 (4H, m), 1.20-1.35 (10H, m), 1.38-1.58 (4H, m), 1.83-1.92 (2H,m), 2.32-2.42 (4H, m), 2.59 (1H, d, J=16.0 Hz), 2.71 (6H, s), 2.89 (1H,d, J=16.0 Hz), 3.04 (1H, dd, J=9.2, 13.8 Hz), 3.19 (1H, d, J=8.0 Hz),3.30-3.35 (1H, m), 4.76 (1H, dd, J=4.4, 9.2 Hz), 5.49-5.53 (2H, m) ,7.37 (2H,d, J=7.6 Hz) , 7.62 (2H,d, J=7.6 Hz), 7.82-7.87 (4H,m)

Example 61

Physicochemical property of Compound 75

Molecular weight 680

ESI (LC/MS positive mode) 681 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.88 (3H, t, J=5.6 Hz),1.14-1.37 (14H, m), 1.42-1.58 (4H, m), 1.88-1.99 (2H, m), 2.31-2.42 (4H,m), 2.62 (1H, d, J=16.0 Hz), 2.89-2.96 (2H, m), 3.14-3.23 (2H, m), 3.25(3H, s), 4.65 (1H, dd, J=4.6, 9.0 Hz), 5.48-5.67 (2H, m), 6.89-6.97 (3H,m), 6.92-6.97 (2H, m), 6.97-7.10 (2H, m), 7.11-7.25 (2H, m)

Example 62

Physicochemical property of Compound 76

Molecular weight 653

ESI (LC/MS positive mode) 654 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.12-1.22 (4H, m), 1.22-1.38 (10H, m), 1.42-1.56 (4H, m), 1.88-1.97 (2H,m), 2.32-2.43 (4H, m), 2.50 (1H, d, J=16.0 Hz), 2.85 (1H, d, J=16.0 Hz),3.06 (1H, dd, J=9.6, 14.2 Hz), 3.18 (1H,d, J=8.4 Hz), 3.31-3.37 (1H, m),4.77 (1H, dd, J=4.6, 9.6 Hz), 5.47-5.59 (2H, m), 7.43 (2H, d, J=8.4 Hz),7.64 (2H, d, J=8.4 Hz), 9.04 (2H, s), 9.11 (1H, s)

Example 63

Physicochemical property of Compound 77

Molecular weight 697

ESI (LC/MS positive mode) 698 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.88 (3H, t, J=7.0 Hz),1.07-1.18 (4H, m), 1.18-1.34 (10H, m), 1.34-1.58 (4H, m), 1.82-1.92 (2H,m), 2.29-2.42 (4H, m), 2.50 (3H, s), 2.62 (1H, d, J=16.0 Hz), 2.91 (1H,d, J=16.0 Hz), 3.00 (1H, dd, J=9.6, 14.2 Hz), 3.21 (1H, d, J=7.6 Hz),3.26-3.31 (1H, m), 4.73 (1H, dd, J=4.8, 9.6 Hz), 5.44-5.53 (2H, m),7.27-7.32 (4H, m), 7.50-7.54 (4H, m)

Example 64

Physicochemical property of Compound 78

Molecular weight 682

ESI (LC/MS positive mode) 683 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.12-1.21 (4H, m), 1.21-1.37 (10H, m), 1.41-1.58 (4H, m), 1.86-1.96 (2H,m), 2.32-2.43 (4H, m), 2.52 (1H, d, J=16.4 Hz), 2.86 (1H, d, J=16.4 Hz),3.05 (1H, dd, J=9.3, 13.9 Hz), 3.17 (1H,d, J=8.3 Hz), 3.32-3.36 (1H, m),3.99 (3H, s), 4.76 (1H, dd, J=4.9, 9.3 Hz), 5.46-5.57 (2H, m), 7.40 (2H,d, J=8.3 Hz), 7.62 (2H, d, J=8.3 Hz), 7.81-7.82 (1H, m), 8.28-8.29 (1H,m), 8.46 (1H, s)

Example 65

Physicochemical property of Compound 79

Molecular weight 670

ESI (LC/MS positive mode) 671 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.15-1.36 (14H, m), 1.41-1.58 (4H, m), 1.87-1.98 (2H, m), 2.23 (3H,s),2.33-2.45 (7H, m), 2.58 (1H, d, J=16.0 Hz), 2.88 (1H, d, J=16.0 Hz),3.03 (1H, dd, J=9.2, 14.0 Hz), 3.21 (1H, d, J=8.4 Hz), 3.30-3.34 (1H,m), 4.73 (1H, dd, J=4.4, 9.2 Hz), 5.49-5.60 (2H, m), 7.24 (1H, d, J=8.4Hz), 7.34 (2H, d, J=8.4 Hz)

Example 66

Physicochemical property of Compound 80

Molecular weight 729

ESI (LC/MS positive mode) 730 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.8 Hz),1.10-1.19 (4H, m), 1.19-1.33 (10H, m), 1.34-1.58 (4H, m), 1.85-1.93 (2H,m), 2.31-2.42 (4H, m), 2.59 (1H, d, J=16.6 Hz), 2.88 (1H, d, J=16.6 Hz),3.04 (1H, dd, J=9.6, 14.0 Hz), 3.14 (3H, s), 3.20 (1H, d, J=7.6 Hz),3.31-3.35 (1H, m), 4.76 (1H, dd, J=4.4, 9.6 Hz), 5.45-5.56 (2H, m), 7.37(2H, d, J=8.2 Hz), 7.62 (2H, d, J=8.2 Hz), 7.86 (2H, d, J=8.6 Hz), 8.00(2H, d, J=8.6 Hz)

Example 67

Physicochemical property of Compound 81

Molecular weight 683

ESI (LC/MS positive mode) 684 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.2 Hz),1.08-1.20 (4H, m), 1.20-1.36 (10H, m), 1.39-1.58 (4H, m), 1.87-1.95 (2H,m), 2.32-2.45 (4H, m), 2.53 (1H, d, J=16.4 Hz), 2.86 (1H, d, J=16.4 Hz),3.03 (1H, dd, J=9.6, 14.2 Hz), 3.19 (1H,d, J=8.0 Hz), 3.31-3.34 (1H, m),4.04 (3H, s), 4.75 (1H, dd, J=4.6, 9.6 Hz), 5.46-5.56 (2H, m), 7.37 (2H,d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 8.79 (2H,s)

Example 68

Physicochemical property of Compound 82

Molecular weight 648

ESI (LC/MS positive mode) 649 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.20-1.40 (14H, m), 1.48-1.58 (4H, m), 1.93-2.02 (2H, m), 2.05-2.16 (2H,m), 2.25 (1H, d, J=16.0 Hz), 2.43 (4H, t, J=7.5 Hz), 2.71 (1H, d, J=16.0Hz), 2.90 (1H, dd, J=14.0, 9.5 Hz), 3.10-3.25 (4H, m), 4.08 (2H, t,J=5.5 Hz), 4.62 (1H, dd, J=9.5, 4.5 Hz), 5.47-5.64 (2H, m), 6.84 (2H, d,J=8.5 Hz), 7.16 (2H, d, J=8.5 Hz)

Example 69

Physicochemical property of Compound 83

Molecular weight 688

ESI (LC/MS positive mode) 689 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.21-1.40 (14H, m), 1.47-1.58 (4H, m), 1.94-2.03 (2H, m), 2.00-2.30 (4H,m), 2.43 (4H, t, J=7.5 Hz), 2.49 (1H, d, J=16.0 Hz), 2.81 (1H, d, J=16.0Hz), 2.89 (3H, s), 2.93 (1H, dd, J=14.0, 9.0 Hz), 3.17 (1H, d, J=8.0Hz), 3.19 (1H, dd, J=14.0, 5.0 Hz), 3.27-3.44 (4H, m), 4.60-4.67 (1H,m), 4.63 (1H, dd, J=9.0, 5.0 Hz), 5.47-5.65 (2H, m), 6.90 (2H, d, J=8.5Hz), 7.18 (2H, d, J=8.5 Hz)

Example 70

Physicochemical property of Compound 84

Molecular weight 676

ESI (LC/MS positive mode) 677 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.21-1.38 (16H, m), 1.47-1.58 (4H, m), 1.94-2.03 (2H, m), 2.15-2.25 (2H,m), 2.22 (1H, d, J=16.0 Hz), 2.43 (4H, t, J=7.5 Hz), 2.71 (1H, d, J=16.0Hz), 2.89 (1H, dd, J=14.0, 9.5 Hz), 2.90 (6H, s), 3.10 (1H, d, J=8.0Hz), 3.22 (1H, dd, J=14.0, 4.5 Hz), 4.08 (2H, t, J=5.5 Hz), 4.63 (1H,dd, J=9.5, 4.5 Hz), 5.47-5.64 (2H, m), 6.83 (2H, d, J=8.5 Hz), 7.16 (2H,d, J=8.5 Hz)

Example 71

Physicochemical property of Compound 85

Molecular weight 682

ESI (LC/MS positive mode) 683 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.19-1.36 (14H, m), 1.43-1.57 (4H, m), 1.93-2.02 (2H, m), 2.37-2.44 (4H,m), 2.53 (1H, d, J=16.0 Hz), 2.87 (1H, d, J=16.0 Hz), 2.92 (1H, dd,J=14.0, 9.0 Hz), 3.18 (1H, d, J=8.0 Hz), 3.19 (1H, dd, J=14.0, 4.5 Hz),4.66 (1H, dd, J=9.0, 4.5 Hz), 5.17 (2H, s), 5.45-5.62 (2H, m), 6.93 (2H,d, J=8.5 Hz), 7.17 (2H, d, J=8.5 Hz), 7.63 (1H, brt, J=8.0 Hz), 8.13(1H, brd, J=8.0 Hz), 8.58 (1H, brs), 8.70 (1H, brs)

Example 72

Physicochemical property of Compound 86

Molecular weight 704

ESI (LC/MS positive mode) 705 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.21-1.39 (14H, m), 1.47-1.58 (4H, m), 1.95-2.03 (2H, m), 2.40-2.46 (4H,m), 2.58 (1H, d, J=15.5 Hz), 2.89 (1H, dd, J=14.0, 10.0 Hz), 3.03 (1H,d, J=7.0 Hz), 3.10-3.48 (8H, m), 3.86-3.92 (4H, m), 4.29-4.39 (2H, m),4.63 (1H, dd, J=10.0, 4.0 Hz), 5.49-5.66 (2H, m), 6.87 (2H, d, J=8.5Hz), 7.19 (2H, d, J=8.5 Hz)

Example 73

Physicochemical property of Compound 87

Molecular weight 703

ESI (LC/MS positive mode) 704 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.22-1.39 (14H, m), 1.47-1.59 (4H, m), 1.95-2.02 (2H, m), 2.34 (1H, d,J=16.0 Hz), 2.43 (4H, t, J=7.5 Hz), 2.73 (1H, d, J=16.0 Hz), 2.86-2.96(7H, m), 3.12 (1H, d, J=8.0 Hz), 3.16-3.22 (5H, m), 4.13 (2H, t, J=5.0Hz), 4.61 (1H, dd, J=9.0, 5.0 Hz), 5.47-5.65 (2H, m), 6.83 (2H, d, J=8.5Hz), 7.16 (2H, d, J=8.5 Hz)

Example 74

Physicochemical property of Compound 88

Molecular weight 739

ESI (LC/MS positive mode) 740 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.18-1.38 (16H, m), 1.46-1.58 (4H, m), 1.92-2.02 (2H, m), 2.10-2.24 (2H,m), 2.43 (4H, t, J=7.5 Hz), 2.67 (1H, d, J=16.0 Hz), 2.89 (1H, dd,J=14.0, 9.5 Hz), 3.06-3.11 (1H, m), 3.21-3.30 (2H, m), 4.09 (2H, brt,J=5.0 Hz), 4.30 (2H, s), 4.62 (1H, dd, J=9.5, 4.5 Hz), 5.47-5.62 (2H,m), 6.82 (2H, d, J=8.5 Hz), 7.15 (2H, d, J=8.5 Hz), 7.48-7.56 (1H, m),7.99 (1H, brd, J=7.5 Hz), 8.61 (1H, brs), 8.66 (1H, brs)

Example 75

Physicochemical property of Compound 89

Molecular weight 731

ESI (LC/MS positive mode) 732 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.20-1.40 (14H, m), 1.48-1.60 (4H, m), 1.92-2.09 (4H, m), 2.43 (4H, t,J=7.5 Hz), 2.77 (3H, s), 2.83-2.98 (8H, m), 3.11-3.26 (7H, m), 4.04 (2H,brt, J=5.5 Hz), 4.63 (1H, dd, J=9.0, 4.5 Hz), 5.43-5.63 (2H, m), 6.81(2H, d, J=8.5 Hz), 7.13 (2H, d, J=8.5 Hz)

Example 76

Physicochemical property of Compound 90

Molecular weight 616

ESI (LC/MS positive mode) 617 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.20-1.40 (14H, m), 1.48-1.59 (4H, m), 1.90-2.00 (2H, m), 2.43 (4H, t,J=7.5 Hz), 2.50 (1H, d, J=16.0 Hz), 2.87 (1H, d, J=16.0 Hz), 2.95 (1H,dd, J=14.0, 9.5 Hz), 3.17 (1H, d, J=8.0 Hz), 3.24 (1H, dd, J=14.0, 4.5Hz), 4.68 (1H, dd, J=9.5, 4.5 Hz), 5.44-5.60 (2H, m), 6.95 (2H, d, J=8.5Hz), 7.25 (2H, d, J=8.5 Hz)

Example 77

Physicochemical property of Compound 91

Molecular weight 826

ESI (LC/MS positive mode) 827 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.88 (3H, t, J=6.5 Hz),1.15-1.35 (14H, m), 1.40-1.55 (4H, m), 1.85-2.00 (2H, m), 2.34-2.40 (4H,m), 2.53 (1H, d, J=16.0 Hz), 2.87 (1H, d, J=16.0 Hz), 2.98 (1H, dd,J=14.0, 9.0 Hz), 3.20 (1H, d, J=8.0 Hz), 3.21 (1H, dd, J=14.0, 4.5 Hz),4.18-4.26 (3H, m), 4.36 (2H, d, J=6.5 Hz), 4.67 (1H, dd, J=9.0, 4.5 Hz),5.45-5.63 (2H, m), 7.17 (4H, s), 7.30 (2H, t, J=7.5 Hz), 7.39 (2H, t,J=7.5 Hz), 7.65 (2H, d, J=7.5 Hz), 7.79 (2H, d, J=7.5 Hz)

Example 78

Physicochemical property of Compound 92

Molecular weight 668

ESI (LC/MS positive mode) 669 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.SHz),1.19-1.39 (14H, m), 1.48-1.58 (4H, m), 1.93-2.04 (2H, m), 2.44 (4H, t,J=7.5 Hz), 2.61 (1H, d, J=16.0 Hz), 2.90 (1H, d, J=16.0 Hz), 2.91 (3H,s), 2.96 (1H, dd, J=14.5, 9.0 Hz), 3.17-3.24 (2H, m), 4.66 (1H, dd,J=9.0, 4.5 Hz), 5.46-5.64 (2H, m), 7.15 (2H, d, J=8.5 Hz), 7.20 (2H, d,J=8.5 Hz)

Example 79

Physicochemical property of Compound 93

Molecular weight 632

ESI (LC/MS positive mode) 633 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.20-1.40 (14H, m), 1.45-1.58 (4H, m), 1.90-2.00 (2H, m), 2.10 (3H, s),2.43 (4H, t, J=7.5 Hz), 2.59 (1H, d, J=16.0 Hz), 2.90 (1H, d, J=16.0Hz), 2.95 (1H, dd, J=14.0, 9.0 Hz), 3.15-3.22 (2H, m), 4.66 (1H, dd,J=9.0, 4.5 Hz), 5.45-5.60 (2H, m), 7.15 (2H, d, J=8.5 Hz), 7.46 (2H, d,J=8.5 Hz)

Example 80

Physicochemical property of Compound 94

Molecular weight 604

ESI (LC/MS positive mode) 605 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.20-1.40 (14H, m), 1.48-1.59 (4H, m), 1.93-2.02 (2H, m), 2.40-2.46 (4H,m), 2.55 (1H, d, J=16.5 Hz), 2.94-3.05 (2H, m), 3.10-3.16 (2H, m), 4.04(2H, s), 4.70 (1H, dd, J=9.5, 4.5 Hz), 5.50-5.65 (2H, m), 7.33 (4H, s)

Example 81

Physicochemical property of Compound 95

Molecular weight 632

ESI (LC/MS positive mode) 633 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=6.5 Hz),1.20-1.40 (14H, m), 1.48-1.59 (4H, m), 1.96-2.04 (2H, m), 2.44 (4H, t,J=7.5 Hz), 2.55 (1H, d, J=16.0 Hz), 2.87 (1H, d, J=16.0 Hz), 3.00 (1H,dd, J=13.5, 9.0 Hz), 3.16-3.30 (2H, m), 4.68. (1H, dd, J=9.0, 4.5 Hz),5.48-5.68 (2H, m), 7.18 (2H, d, J=8.0 Hz), 7.34 (2H, d, J=8.0 Hz)

Example 82

Physicochemical property of Compound 96

Molecular weight 714

ESI (LC/MS positive mode) 715 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.15-1.33 (14H, m), 1.41 (3H, t, J=7.0 Hz), 1.46-1.56 (4H, m), 1.85-1.95(2H, m), 2.37-2.46 (4H, m), 2.52 (1H, d, J=16.0 Hz), 2.88 (1H, d, J=16.0Hz), 3.08 (1H, dd, J=14.0, 9.5 Hz), 3.17 (1H, d, J=8.0 Hz), 3.38 (1H,dd, J=14.0, 4.5 Hz), 4.42 (2H, q, J=7.0 Hz), 4.79 (1H, dd, J=9.5, 4.5Hz), 5.42-5.60 (2H, m), 7.47 (2H, d, J=8.5 Hz), 7.82 (2H, d, J=8.5 Hz),9.09 (1H, s)

Example 83

Physicochemical property of Compound 97

Molecular weight 576

ESI (LC/MS positive mode) 577 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.20-1.40 (14H, m), 1.45-1.58 (4H, m), 1.93-2.03 (2H, m), 2.41-2.46 (4H,m), 2.51 (1H, d, J=16.0 Hz), 2.89 (1H, d, J=16.0 Hz), 3.13 (1H, dd,J=14.0, 9.5 Hz), 3.18 (1H, d, J=8.0 Hz), 3.39 (1H, dd, J=14.0, 5.0 Hz),4.78 (1H, dd, J=9.5, 5.0 Hz), 5.46-5.64 (2H, m), 7.61 (1H, dd, J=8.0,5.5 Hz), 8.06 (1H, d, J=8.0 Hz), 8.52 (1H, d, J=5.5 Hz), 8.57 (1H, s)

Example 84

Physicochemical property of Compound 98

Molecular weight 665

LC-MS (ESI, positive mode) 666 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.96 (6H, d, J=7.0 Hz),1.22-1.46 (10H, m), 1.48-1.75 (8H, m), 1.75-1.90 (1H, m), 1.93-2.00 (2H,m), 2.40-2.48 (4H, m), 2.58 (1H, d, J=16.0 Hz), 2.89 (1H, d, J=16.0 Hz),2.90 (1H, dd, J=14.0, 9.0 Hz), 3.15 (1H, dd, J=14.0, 5.0 Hz), 3.19 (1H,d, J=8.0 Hz), 3.95 (2H, t, J=6.5 Hz), 4.40 (2H, dt, J=47.5, 6.0 Hz),4.63 (1H, dd, J=9.0, 5.0 Hz), 5.45-5.61 (2H, m), 6.79 (2H, d, J=8.5 Hz),7.11 (2H, d, J=8.5 Hz)

Example 85

Physicochemical property of Compound 99

Molecular weight 677

LC-MS (ESI, positive mode) 678 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.96 (6H, d, J=6.3 Hz),1.26-1.38 (10H, m), 1.45-1.59 (6H, m), 1.64 (2H, q, J=6.8 Hz), 1.78-1.88(1H, m), 1.94-1.98 (2H, m), 2.41-2.46 (4H, m), 2.58 (1H, d, J=16.0 Hz),2.89 (1H, d, J=16.0 Hz), 2.88-2.93 (1H, m), 3.16 (1H, dd, J=14.0, 4.9Hz), 3.19 (1H, d, J=8.3 Hz), 3.31 (3H, s), 3.34 (2H, t, J=6.3 Hz), 3.95(2H, t, J=6.3 Hz), 4.62-4.67 (1H, m), 5.47-5.59 (2H, m), 6.79 (2H, d,J=8.8 Hz), 7.10 (2H, d, J=8.8 Hz)

Example 86

Physicochemical property of Compound 100

Molecular weight 651

ESI (LC/MS positive mode) 652 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=7.0 Hz),1.19-1.41 (14H, m), 1.43-1.54 (4H, m), 1.85-1.96 (2H, m), 2.30-2.39 (4H,m), 2.64 (1H, d, J=16.0 Hz), 2.90 (1H, d, J=16.0 Hz), 2.97-3.04 (1H, m),3.19-3.26 (2H, m), 4.70-4.78 (1H, m), 5.44-5.59 (2H, m), 7.28-7.32 (3H,m), 7.42 (2H, t, J=7.5 Hz), 7.52-7.61 (4H, m)

Example 87

Physicochemical property of Compound 101

Molecular weight 667

ESI (LC/MS positive mode) 668 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.19-1.37 (14H, m), 1.44-1.56 (4H, m), 1.91-1.98 (2H, m), 2.36-2.43 (4H,m), 2.62 (1H, d, J=16.0 Hz), 2.92 (1H, d, J=16.0 Hz), 2.96 (1H, dd,J=14.0, 9.5 Hz), 3.19-3.26 (2H, m), 4.74 (1H, dd, J=9.5, 5.0 Hz),5.45-5.61 (2H, m), 6.87 (2H, d, J=8.5 Hz), 6.95 (2H, d, J=7.5 Hz), 7.08(1H, t, J=7.5 Hz), 7.20 (2H, d, J=8.5 Hz), 7.33 (2H, t, J=7.5 Hz)

Example 88

Physicochemical property of Compound 102

Molecular weight 637

ESI (LC/MS positive mode) 638 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=6.5 Hz),1.15-1.35 (12H, m), 1.43-1.57 (4H, m), 1.87-1.95 (2H, m), 2.27-2.47 (4H,m), 2.62 (1H, d, J=16.0 Hz), 2.91 (1H, d, J=16.0 Hz), 3.02 (1H, dd,J=14.0, 9.0 Hz), 3.21 (1H, d, J=8.0 Hz), 3.28 (1H, dd, J=14.0, 4.5 Hz),4.73 (1H, dd, J=9.0, 4.5 Hz), 5.44-5.60 (2H, m), 7.27-7.33 (3H, m), 7.41(2H, t, J=7.5 Hz), 7.51-7.60 (4H, m)

Example 89

Physicochemical property of Compound 103

Molecular weight 653

ESI (LC/MS positive mode) 654 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.89 (3H, t, J=6.5 Hz),1.14-1.37 (12H, m), 1.44-1.57 (4H, m), 1.91-2.00 (2H, m), 2.37-2.44 (4H,m), 2.62 (1H, d, J=16.0 Hz), 2.92 (1H, d, J=16.0 Hz), 2.96 (1H, dd,J=14.0, 9.0 Hz), 3.22 (1H, d, J=8.5 Hz), 3.22 (1H, dd, J=14.0, 4.5 Hz),4.67 (1H, dd, J=9.0, 4.5 Hz), 5.46-5.64 (2H, m), 6.87 (2H, d, J=8.5 Hz),6.94 (2H, d, J=7.5 Hz), 7.08 (1H, t, J=7.5 Hz), 7.20 (2H, d, J=8.5 Hz),7.33 (2H, t, J=7.5 Hz)

Example 90

Physicochemical property of Compound 104

Molecular weight 671

ESI (LC/MS positive mode) 672 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=6.5 Hz),0.96 (3H, t, J=7.5 Hz), 1.22-1.37 (14H, m), 1.44-1.59 (6H, m), 1.93-2.03(2H, m), 2.15-2.22 (2H, m), 2.44 (4H, t, J=7.5 Hz), 2.57 (1H, d, J=16.0Hz), 2.89 (1H, d, J=16.0 Hz), 2.93 (1H, dd, J=14.0, 9.0 Hz), 3.17-3.20(1H, m), 3.20 (1H, d, J=7.5 Hz), 4.61-4.66 (3H, m), 5.46-5.62 (2H, m),6.86 (2H, d, J=8.5 Hz), 7.13 (2H, d, J=8.5 Hz)

Example 91

Physicochemical property of Compound 105

Molecular weight 629

ESI (LC/MS positive mode) 630 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=6.5 Hz),1.20-1.40 (14H, m), 1.48-1.59 (4H, m), 1.93-2.03 (2H, m), 2.44 (4H, t,J=7.5 Hz), 2.56 (1H, d, J=16.0 Hz), 2.89 (1H, d, J=16.0 Hz), 2.90-2.97(2H, m), 3.18 (1H, dd, J=14.0, 4.5 Hz), 3.19 (1H, d, J=8.0 Hz), 4.64(1H, dd, J=9.0, 4.5 Hz), 4.67 (2H, d, J=2.5 Hz), 5.46-5.62 (2H, m), 6.87(2H, d, J=8.5 Hz), 7.14 (2H, d, J=8.5 Hz)

Example 92

Physicochemical property of Compound 106

Molecular weight 657

ESI (LC/MS positive mode) 658 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=6.5 Hz),1.20-1.40 (14H, m), 1.46-1.59 (4H, m), 1.89-1.99 (4H, m), 2.24 (1H, t,J=2.5 Hz), 2.33-2.46 (6H, m), 2.58 (1H, d, J=16.0 Hz), 2.89 (1H, d,J=16.0 Hz), 2.93 (1H, dd, J=14.0, 9.0 Hz), 3.13-3.22 (2H, m), 4.02 (2H,t, J=6.0 Hz), 4.64 (1H, dd, J=9.0, 4.5 Hz), 5.45-5.61 (2H, m), 6.81 (2H,d, J=8.5 Hz), 7.12 (2H, d, J=8.5 Hz)

Example 93

Physicochemical property of Compound 107

Molecular weight 657

ESI (LC/MS positive mode) 658 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=6.5 Hz),1.20-1.39 (14H, m), 1.46-1.59 (4H, m), 1.75 (3H, t, J=2.5 Hz), 1.90-2.00(2H, m), 2.39-2.48 (4H, m), 2.50-2.60 (3H, m), 2.85-2.95 (2H, m), 3.16(1H, dd, J=14.0, 4.5 Hz), 3.18-3.22 (1H, m), 3.97 (2H, t, J=7.0 Hz),4.63 (1H, dd, J=9.0, 4.5 Hz), 5.45-5.61 (2H, m), 6.80 (2H, d, J=8.5 Hz),7.12 (2H, d, J=8.5 Hz)

Example 94

Physicochemical property of Compound 108

Molecular weight 714

ESI (LC/MS positive mode) 715 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=7.0 Hz),1.26-1.38 (20H, m), 1.50-1.57 (4H, m), 1.94-2.03 (2H, m), 2.44 (4H, t,J=7.5 Hz), 2.55 (1H, d, J=16.0 Hz), 2.87 (1H, d, J=16.0 Hz), 2.92 (1H,dd, J=14.0, 9.0 Hz), 3.17-3.20 (2H, m), 3.21 (4H, q, J=7.5 Hz), 4.15(2H, t, J=2.0 Hz), 4.65 (1H, dd, J=9.0, 4.5 Hz), 4.84 (2H, t, J=2.0 Hz),5.48 (1H, dd, J=15.0, 9.0 Hz), 5.59 (1H, dt, J=15.0, 6.5 Hz), 6.90 (2H,d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz)

Example 95

Physicochemical property of Compound 109

Molecular weight 657

ESI (LC/MS positive mode) 658 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=6.5 Hz),1.11 (3H, t, J=7.5 Hz), 1.20-1.38 (14H, m), 1.48-1.59 (4H, m), 1.93-2.01(2H, m), 2.16-2.26 (2H, m), 2.44 (4H, t, J=7.0 Hz), 2.58 (1H, d, J=16.0Hz), 2.89 (1H, d, J=16.0 Hz), 2.92 (1H, dd, J=14.0, 9.0 Hz), 3.17 (1H,dd, J=14.0, 4.5 Hz), 3.20 (1H, d, J=8.0 Hz), 4.62 (2H, t, J=2.0 Hz),4.63-4.66 (1H, m), 5.45-5.62 (2H, m), 6.85 (2H, d, J=8.5 Hz), 7.13 (2H,d, J=8.5 Hz)

Example 96

Physicochemical property of Compound 110

Molecular weight 727

ESI (LC/MS positive mode) 728 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (6H, t, J=6.5 Hz),1.20-1.59 (28H, m), 1.93-2.01 (2H, m), 2.17-2.23 (2H, m), 2.44 (4H, t,J=7.0 Hz), 2.64 (1H, d, J=16.5 Hz), 2.89 (1H, d, J=16.5 Hz), 2.92 (1H,dd, J=14.0, 9.0 Hz), 3.17 (1H, dd, J=14.0, 4.5 Hz), 3.20 (1H, d, J=7.5Hz), 4.63 (2H, t, J=2.0 Hz), 4.63-4.66 (1H, m), 5.45-5.61 (2H, m), 6.85(2H, d, J=8.5 Hz), 7.13 (2H, d, J=8.5 Hz)

Example 97

Physicochemical property of Compound 111

Molecular weight 709

ESI (LC/MS positive mode) 710 (M+H⁺)

¹H-NMR (in methanol d-4) chemical shift value δ: 0.90 (3H, t, J=6.5 Hz),1.23 (9H, s), 1.24-1.40 (14H, m), 1.46-1.59 (4H, m), 1.93-2.02 (2H, m),2.44 (4H, t, J=7.0 Hz), 2.58 (1H, d, J=16.0 Hz), 2.90 (1H, d, J=16.0Hz), 2.93 (1H, dd, J=14.0, 9.0 Hz), 3.19 (1H, dd, J=14.0, 4.5 Hz), 3.20(1H, d, J=8.0 Hz), 4.65 (1H, dd, J=9.0, 4.5 Hz), 4.74 (2H, s), 5.51-5.61(2H, m), 6.86 (2H, d, J=8.5 Hz), 7.15 (2H, d, J=8.5 Hz)

Preparation Example 1

In Preparation example 1, a synthesis method for the compound used inStep 1-7 in the preparation of the compound of the formula (I) isexplained.Step 2-1

8-Nonynoic acid (50 g, 0.32 mol) was added dropwise to a solution ofN,O-dimethylhydroxylamine hydrochloride (63.3 g, 0.65 mol),water-soluble carbodiimide hydrochloride (WSC HCl) (124 g, 0.65 mol),1-hydroxybenzotriazole (HOBt) (99.3 g, 0.65 mol) andN,N-diisopropylethylamine (DIPEA) (220 ml, 1.3 mol) in dichloromethane(500 ml) at 0° C. and the mixture was stirred at room temperature for 15hours. The reaction solution was washed with a saturated aqueousammonium chloride solution (400 ml), a saturated aqueous sodiumhydrogencarbonate solution (400 ml) and saturated brine (300 ml). Afterthe organic layer was dehydrated and dried with anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. The thusobtained residue was purified by column chromatography (Wako gel C-300,500 g, Wako Pure Chemical). Compound 112 (60 g, 94%) was obtained froman elution part of hexane/ethyl acetate (20:1) as a colorless oil.

Physicochemical properties of Compound 112

Molecular weight: 197

ESI (LC/MS positive mode) 198 (M+H⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 1.30-1.70 (8H,m), 1.94 (1H, t, J=2.5 Hz), 2.19 (2H, dt, J=2.5, 7 Hz), 2.42 (2H, t,J=7.5 Hz), 3.18 (3H, s), 3.68 (3H, s)Step 2-2

A 1M solution of n-heptylmagnesium bromide in diethyl ether (100 ml, 0.1mol) was added dropwise to a solution of the above Compound 112 (7 g,0.035 mol) in tetrahydrofuran (100 ml) at −10° C. and the mixture wasstirred at the same temperature for 2 hours and 30 minutes. A saturatedaqueous ammonium chloride solution (30 ml) was added to the reactionsolution and water (100 ml) was further added thereto, followed bystirring of the mixture at room temperature for 10 minutes. The mixturewas diluted with water (300 ml) and extracted twice with ethyl acetate(400 ml). The organic layer was combined, washed with saturated brine(30 ml) and dehydrated and dried with anhydrous sodium sulfate, followedby distilling off of the solvent under reduced pressure. The residue waspurified by column chromatography (Wako gel C-300, 250 g, Wako PureChemical). The Compound 113 (7.8 g, 93%) was obtained from an elutionpart of hexane/ethyl acetate (100:1) as a colorless oil.

Physicochemical properties of Compound 113

Molecular weight: 236

EI-MS 236 (M⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 0.88 (3H, t,J=6.5 Hz), 1.23-1.63 (18H, m), 1.94 (1H, dt, J=0.5, 2.5 Hz), 2.18 (2H,dt, J=2.5, 7 Hz), 2.36-2.42 (4H, m)Step 2-3

The above Compound 113 (7.8 g, 0.033 mol), ethylene glycol (18 ml, 0.33mol) and toluenesulfonic acid monohydrate (125 mg, 0.66 mmol) were addedto benzene (150 ml) and reflux condenser equipped with Dien-Staak waterseparator was attached, followed by heating under reflux for 20 hours.After the reaction solution was allowed to cool, the reaction solutionwas washed with a saturated aqueous sodium hydrogencarbonate solution(30 ml), water (50 ml) and then saturated brine (50 ml). The organiclayer was dehydrated and dried with anhydrous sodium sulfate and thesolvent was distilled off under reduced pressure. The thus obtainedresidue was purified by Mega Bond Elut SI (10 g, Barian Inc.). Compound114 (8.9 g, 97%) was obtained from an elution part of hexane/ethylacetate (20:1) as a colorless oil.

Physicochemical properties of Compound 114

Molecular weight: 280

EI-MS 280 (M⁺)

¹H-NMR (in deutero chloroform) chemical shift value δ: 0.88 (3H, t,J=6.5 Hz), 1.23-1.63 (22H, m), 1.93 (1H, t, J=2.5 Hz), 2.18 (2H, dt,J=2.5, 7 Hz), 3.92 (4H, s)

Test Example 1

Replicon Assay

A construct was prepared in which a luciferase gene derived from fireflywas introduced as a reporter gene in HCV-RNA to assay the number ofcopies of HCV-RNA. The luciferase gene was introduced in the form offusing with neomycin-resistance gene directly below the IRES (InternalRibosome Entry Site) of the HCV gene in accordance with the method ofKrieger, et al. (J. Virol. 75:4614). After synthesizing this RNA invitro, it was introduced into Huh7 cell by electroporation and isolatedas G418-resistant clone. Firefly luciferase HCV replicon cells (3-1)were suspended in Dulbecco's MEM (Gibco cat. no. 10569-010) containing5% fetal bovine serum (Hyclone cat. no. SH30071.03), inoculated into thewells of a 96-well plate at 5000 cells/well and then cultured overnightat 37° C. and 5% Co₂. Approximately 20 hours later, the diluted testcompound was added at 10 μl per well followed by culturing for another 3days. Two series of assay plates were prepared, and the assay wascarried out using a white plate for one series and a clear plate for theother series. Following completion of culturing, the white plate wasused for the Steady-Glo Luciferase Assay System (Promega cat. no.E2520). Namely, after adding 100 tl of reagent per well, mixing by apipette 3 to 4 times and then allowing to stand for 5 minutes,luminescence was measured with the 1450 MicroBeta TRILUX (Wallac) .Values obtained in the absence of cell addition were used as backgroundvalues and subtracted from all values to calculate the IC₅₀ (50%inhibitory concentration) of the drug based on a value of 0% inhibitionfor the value in the absence of addition of test compound.

Test Example 2

Cytotoxicity Test

The Cell Counting Kit 8 (Dojindo cat. no. CK04) was used to determinethe cytotoxicity. Namely, 10 μl of Cell Counting Kit 8 were added to aclear plate and incubated for 30 to 60 minutes at 37° C. Absorbance at awavelength of 450 nm and a control wavelength of 630 nm was measuredwith a 96-well plate reader. Values in the absence of cell addition wereused as background values and subtracted from all values to calculatethe CC₅₀ (50% cell inhibitory concentration) of the drug based on avalue of 0% inhibition for the value in the absence of addition of drug.

The results of Text Examples 1 and 2 are shown below. Biologicalactivity Compound Replicon IC50 Cytotoxicity No. [uM] CC50 [uM] 150.002 >5 16 0.010 >5 17 <0.001 >5 18 0.001 >5 19 0.002 >5 20 0.007 >5 210.004 >1 22 0.014 >1 23 0.017 >1 24 0.011 >1 25 0.009 >1 26 0.017 >1 270.010 >1 28 0.009 >1 29 0.006 >1 30 0.008 >1 31 0.012 >1 32 0.068 >1 330.012 >1 34 0.055 >1 35 0.080 >1 36 0.500 >1 37 0.210 >1 38 0.024 >1 390.020 >1 40 0.001 >1 41 0.002 >1 42 0.001 >1 43 0.003 >1 44 0.001 >1 450.005 >1 46 0.800 >5 47 0.250 >1 48 0.003 >1 49 0.004 >1 50 0.004 >1 510.017 >1 52 0.024 >1 53 0.002 >1 54 0.002 >1 55 0.019 >1 56 0.006 >1 570.011 >1 58 0.004 >1 59 0.003 >1 60 0.008 >1 61 0.006 >1 62 0.002 >1 630.010 >1 64 0.007 >1 65 0.002 >1 66 0.006 >1 67 0.004 >1 68 0.002 >1 690.002 >1 70 0.011 >1 71 0.004 >1 72 0.006 >1 73 0.002 >1 74 0.135 >1 750.006 >1 76 0.013 >1 77 0.007 >1 78 0.003 >1 79 0.104 >1 80 0.071 >1 810.008 >1 82 0.039 >1 83 0.108 >1 84 0.043 >1 85 0.001 >1 86 0.007 >1 870.038 >1 88 0.018 >1 89 0.029 >1 90 0.006 >1 91 0.008 >1 92 0.002 >1 930.012 >1 94 0.280 >1 95 0.395 >1 96 0.009 >1 97 0.302 >1 98 0.021 >1 990.056 >1 100 0.092 >1 101 0.046 >1 102 0.005 >1 103 0.011 >1 1040.001 >1 105 0.003 >1 106 0.001 >1 107 0.001 >1 108 0.003 >1 1090.002 >1 110 0.005 >1 111 0.006 >1

INDUSTRIAL APPLICABILITY

The compounds of the present invention have extremely potent anti-HCVactivity and HCV growth inhibitory effects, and since they also onlydemonstrate subtle cytotoxicity in vitro, a pharmaceutical compositioncontaining the compound of the present invention is extremely useful asan anti-HCV preventive/therapeutic agent.

1. A method for producing a compound represented by formula (I):

(wherein A represents —(CH₂)_(n)—, where n represents an integer of 0 to10; B represents —CH₂—, —(C═O)—, —CH(OH)—, —CH(NH₂)— or —C(═NOR)—, whereR represents a hydrogen atom, a linear or branched alkyl group having 1to 8 carbon atoms (which may be substituted with an amino group that maybe mono- or di-substituted with a linear or branched alkyl group having1 to 4 carbon atoms); D represents —(CH₂)_(m)—R′, where m represents aninteger of 0 to 10, and R′ represents a hydrogen atom, a linear orbranched alkyl group, a linear or branched alkynyl group, a linear orbranched alkenyl group, a cycloalkyl group, a cycloalkenyl group, aheterocyclyl group which may be substituted, an aryl group which may besubstituted, a heteroaryl group which may be substituted, an —OX group(where X represents a hydrogen atom, a linear or branched alkyl group, alinear or branched alkynyl group, a linear or branched alkenyl group, acycloalkyl group or an aryl group which may be substituted) or a halogenatom; E represents a hydrogen atom or a linear or branched alkyl group;G represents —(CH₂)_(p)-J, where p represents an integer of 0 to 4, andJ represents a hydrogen atom, an OH group, a SH group, a methylthiogroup, a carboxyl group, a carbamoyl group, an amino group, a guanidinogroup, a linear or branched alkyl group, a cycloalkyl group, a linear orbranched alkynyl group, a linear or branched alkenyl group, an arylgroup which may be substituted, a heterocyclyl group which may besubstituted, or a heteroaryl group which may be substituted; bond Qrepresents a single bond or a double bond; and R₁, R₂ and R₃ may be thesame or different, and each represent a hydroxyl group, an amino group(which may be mono- or di-substituted with a linear or branched alkylgroup having 1 to 4 carbon atoms), —OL, a linear or branched alkylgroup, a linear or branched alkenyl group or a linear or branchedalkynyl group, where L represents a linear or branched alkyl group, alinear or branched alkenyl group or a linear or branched alkynyl group),a prodrug thereof or a pharmaceutically acceptable salt thereof;comprising reacting a compound as the starting compound represented bythe following formula:

(wherein A, D and bond Q have the same meanings as defined above, and Xand Y may be the same or different and each represent a linear orbranched alkyl group or a protecting group of a carboxyl group) with ana-amino acid ester represented by the following formula:

(wherein E and G have the same meanings as defined above, and Zrepresents of a linear or branched alkyl group or a protecting group ofa carboxyl group) in the presence of a base and a coupling agent, toyield a compound represented by the following formula:

(wherein A, D, E, G, bond Q, X, Y and Z have the same meanings asdefined above), and then subjecting this compound to hydrolysis,reduction, amination or amidation, hydroxyimination and/or esterconversion, if desired, to obtain the desired compound of the formula(I).
 2. A method for producing a compound represented by the followingformula:

(wherein D and n have the same meanings as defined in claim 1, M₁ and M₂may be the same or different and each represent an oxygen atom or asulfur atom, and P and P′ may be the same or different and eachrepresent a hydroxyl protecting group); comprising reacting a compoundrepresented by the following formula:

(wherein P and P′ have the same meanings as defined above) with acompound represented by the following formula:

(wherein D, n, M₁ and M₂ have the same meanings as defined above).
 3. Acompound represented by formula (I):

(wherein A, B, D, E, G, bond Q, R₁, R₂ and R₃ have the same meanings asdefined in claim 1), a prodrug thereof or a pharmaceutically acceptablesalt thereof.
 4. The compound of the formula (I) according to claim 3, aprodrug thereof or a pharmaceutically acceptable salt thereof, whereinin the case n represents 6, D represents a n-heptyl group and prepresents 1, then J represents a group which is neither a phenylgroup(the phenyl group is substituted with an —OW group at thep-position where W represents a hydrogen atom, a linear or branchedalkyl group, or a linear or branched alkenyl group) nor a 3-indolylgroup.
 5. The compound of the formula (I) according to claim 3, aprodrug thereof or a pharmaceutically acceptable salt thereof, whereinin the case n represents 6, D represents a n-heptyl group and prepresents 1, then J represents a group which is neither a phenyl group(the phenyl group is substituted with an —OW group at the p-positionwhere W represents a hydrogen atom, a linear or branched alkyl group, alinear or branched alkenyl group or a linear or branched alkynyl group)nor a 3-indolyl group.
 6. A compound represented by the followingformula:

(wherein P and P′ may be the same or different and each represent ahydroxyl protecting group).
 7. A compound represented by the followingformula:

(wherein A, D, X and Y have the same meanings as defined in claim 1). 8.A pharmaceutical composition containing a compound of the formula (I)according to claim 1, a prodrug thereof or a pharmaceutically acceptablesalt thereof.
 9. The pharmaceutical composition according to claim 8 forpreventing or treating a viral infectious disease.
 10. Thepharmaceutical composition according to claim 9 wherein the viralinfectious disease is an infectious disease by HCV.
 11. Thepharmaceutical composition according to claim 10, wherein the infectiousdisease by HCV is hepatitis C, cirrhosis, liver fibrosis or livercancer.